Apparatus, systems, and methods for achieving intravascular, thermally-induced renal neuromodulation

ABSTRACT

Apparatus, systems, and methods for achieving thermally-induced renal neuromodulation by intravascular access are disclosed herein. One aspect of the present application, for example, is directed to apparatuses, systems, and methods that incorporate a treatment device comprising an elongated shaft. The elongated shaft is sized and configured to deliver a thermal element to a renal artery via an intravascular path. Thermally-induced renal neuromodulation may be achieved via direct and/or via indirect application of thermal energy to heat or cool neural fibers that contribute to renal function, or of vascular structures that feed or perfuse the neural fibers.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/545,648, filed Aug. 21, 2009, which claims the benefit ofthe following pending applications:

(a) U.S. Provisional Patent Application No. 61/142,128, filed on Dec.31, 2008;

(c) European Patent Application No. 09167937.3, filed Aug. 14, 2009;

(d) European Patent Application No. 09168202.1, filed Aug. 14, 2009; and

(e) European Patent Application No. 09168204.7, filed Aug. 14, 2009.

All of these applications are incorporated herein by reference in theirentireties.

U.S. patent application Ser. No. 12/545,648, filed Aug. 21, 2009, isalso a continuation-in-part of U.S. patent application Ser. No.12/494,691, filed Jun. 30, 2009, which claims priority to U.S.Provisional Application No. 61/142,128, filed Dec. 31, 2008.

TECHNICAL FIELD

The technologies disclosed in the present application generally relateto apparatus, systems, and methods for intravascular neuromodulation.More particularly, the technologies disclosed herein relate toapparatus, systems, and methods for achieving intravascular renalneuromodulation via thermal heating.

BACKGROUND

Hypertension, heart failure and chronic kidney disease represent asignificant and growing global health issue. Current therapies for theseconditions include non-pharmacological, pharmacological and device-basedapproaches. Despite this variety of treatment options the rates ofcontrol of blood pressure and the therapeutic efforts to preventprogression of heart failure and chronic kidney disease and theirsequelae remain unsatisfactory. Although the reasons for this situationare manifold and include issues of non-compliance with prescribedtherapy, heterogeneity in responses both in terms of efficacy andadverse event profile, and others, it is evident that alternativeoptions are required to supplement the current therapeutic treatmentregimes for these conditions.

Reduction of sympathetic renal nerve activity (e.g., via denervation),can reverse these processes. Ardian, Inc. has discovered that an energyfield, including and comprising an electric field, can initiate renalneuromodulation via denervation caused by irreversible electroporation,electrofusion, apoptosis, necrosis, ablation, thermal alteration,alteration of gene expression or another suitable modality.

SUMMARY

The following summary is provided for the benefit of the reader only,and is not intended to limit the disclosure in any way. The presentapplication provides apparatus, systems and methods for achievingthermally-induced renal neuromodulation by intravascular access.

One aspect of the present application provides apparatuses, systems, andmethods that incorporate a treatment device comprising an elongatedshaft. The elongated shaft is sized and configured to deliver a thermalheating element to a renal artery via an intravascular path thatincludes a femoral artery, an iliac artery, and the aorta. Differentsections of the elongated shaft serve different mechanical functionswhen in use. The sections are differentiated in terms of their size,configuration, and mechanical properties for (i) percutaneousintroduction into a femoral artery through a small-diameter access site;(ii) atraumatic passage through the tortuous intravascular path throughan iliac artery, into the aorta, and into a respective left/right renalartery, including (iii) accommodating significant flexure at thejunction of the left/right renal arteries and aorta to gain entry intothe respective left or right renal artery; (iv) accommodating controlledtranslation, deflection, and/or rotation within the respective renalartery to attain proximity to and a desired alignment with an interiorwall of the respective renal artery; and (v) allowing the placement of athermal heating element into contact with tissue on the interior wall inan orientation that optimizes the active surface area of the thermalheating element.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is an anatomic interior view of a thoracic cavity of a human,with the intestines removed, showing the kidneys and surroundingstructures.

FIG. 1B in an anatomic view of the urinary system of a human, of whichthe kidneys shown in FIG. 1A form a part.

FIGS. 2A, 2B, and 2C are a series of enlarged anatomic views showingvarious interior regions of a human kidney.

FIG. 3A is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 3B is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 3C and 3D provide anatomic and conceptual views of a human body,respectively, depicting neural efferent and afferent communicationbetween the brain and kidneys

FIGS. 4A and 4B are, respectively, anatomic views of the arterial andvenous vasculatures of a human.

FIG. 5 is a perspective view of a system for achieving intravascular,thermally-induced renal neuromodulation, comprising a treatment deviceand a generator.

FIGS. 6A and 6B are anatomic views of the intravascular delivery,deflection and placement of the treatment device shown in FIG. 5 throughthe femoral artery and into a renal artery.

FIGS. 7A to 7D are a series of views of the elongated shaft of thetreatment device shown in FIG. 5, showing the different mechanical andfunctional regions that the elongated shaft incorporates.

FIG. 7E shows an anatomic view of the placement of the treatment deviceshown in FIG. 5 within the dimensions of the renal artery.

FIG. 8A to 8C show the placement of a thermal heating element, which iscarried at the distal end of the elongated shaft of the treatment deviceshown in FIG. 5, into contact with tissue along a renal artery.

FIGS. 9A and 9B show placement of the thermal heating element shown inFIGS. 8A to 8C into contact with tissue along a renal artery anddelivery of thermal treatment to the renal plexus.

FIGS. 10A and 10B show a representative embodiment of the forcetransmitting section of the elongated shaft of the treatment deviceshown in FIG. 5.

FIGS. 11A to 11C show a representative embodiment of the proximalflexure zone of the elongated shaft of the treatment device shown inFIG. 5.

FIGS. 12A to 12D show a representative embodiment of the intermediateflexure zone of the elongated shaft of the treatment device shown inFIG. 5.

FIGS. 13A to 13C show alternative embodiments of the intermediateflexure zone of the elongated shaft of the treatment device shown inFIG. 5.

FIGS. 14A to 14C show alternative embodiments of the intermediateflexure zone of the elongated shaft of the treatment device shown inFIG. 5.

FIGS. 15A to 15C show a representative embodiment of the distal flexurezone of the elongated shaft of the treatment device shown in FIG. 5.

FIGS. 15D to 15F show multiple planar views of the bending capability ofthe distal flexure zone corresponding to the elongated shaft of thetreatment device shown in FIG. 5.

FIGS. 15G and 15H show alternative embodiments of the distal flexurezone corresponding to the elongated shaft of the treatment device shownin FIG. 5.

FIGS. 15I and 15J show an alternative catheter embodiment of thetreatment device shown in FIG. 5 comprising an intermediate sectioncomprising an arch wire.

FIGS. 16A and 16B show a representative embodiment of a rotationalcontrol mechanism coupled to the handle of the treatment device shown inFIG. 5.

FIGS. 16C and 16D show a handle of the treatment device shown in FIG. 5with a rotational control mechanism having a rotational limiting elementand an actuator lever.

FIGS. 17A and 17B show an alternative representative embodiment of anelongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different mechanical and functional regions thatthe elongated shaft can incorporate.

FIGS. 18A and 18B show another alternative representative embodiment ofan elongated shaft for a treatment device like that shown in FIG. 5,showing examples of the different mechanical and functional regions thatthe elongated shaft can incorporate.

FIGS. 19A to 19H show the intravascular delivery, placement, deflection,rotation, retraction, repositioning and use of a treatment device, likethat shown in FIG. 5, to achieve thermally-induced renal neuromodulationfrom within a renal artery.

FIGS. 19I to 19K show the circumferential treatment effect resultingfrom intravascular use of a treatment device, like that shown in FIG. 5.

FIG. 19L shows an alternative intravascular treatment approach using thetreatment device shown in FIG. 5.

FIG. 20 shows an energy delivery algorithm corresponding to the energygenerator of the system shown in FIG. 5.

FIG. 21 shows several components of the system and treatment deviceshown in FIG. 5 packaged within a single kit.

FIGS. 22A to 22C show fluoroscopic images of the treatment device shownin FIG. 5 in multiple treatment positions within a renal artery.

DETAILED DESCRIPTION

Although the disclosure hereof is detailed and exact to enable thoseskilled in the art to practice the disclosed technologies, the physicalembodiments herein disclosed merely exemplify the various aspects of theinvention, which may be embodied in other specific structure. While thepreferred embodiment has been described, the details may be changedwithout departing from the invention, which is defined by the claims.

I. Pertinent Anatomy and Physiology

A. The Kidneys

FIG. 1A is an anatomic view of the posterior abdominal wall, showing theleft and right kidneys, neighboring organs, and major blood vessels. InFIG. 1A, most of the digestive system located within the peritoneum hasbeen omitted for clarity.

In humans, the kidneys are located in the posterior part of theabdominal cavity. There are two, one on each side of the spine. Theright kidney sits just below the diaphragm and posterior to the liver.The left kidney sits below the diaphragm and posterior to the spleen.The asymmetry within the abdominal cavity caused by the liver results inthe right kidney being slightly lower than the left one, while the leftkidney is located slightly more medial.

Above each kidney is an adrenal gland (also called the suprarenalgland). The adrenal glands make hormones, such as (1) cortisol, which isa natural steroid hormone; (2) aldosterone, which is a hormone thathelps to regulate the body's water balance; and (3) adrenalin andnoradrenaline.

The kidneys are complicated organs that have numerous biological roles.

1. The Blood Filtration Functions

As FIG. 1B shows, the kidneys are part of the body system called theurinary system, which comprises the kidneys, ureters, bladder, andurethra. Generally speaking, the urinary system filters waste productsout of the blood and makes urine.

A primary role of the kidneys is to maintain the homeostatic balance ofbodily fluids by filtering and secreting metabolites (such as urea) andminerals from the blood and excreting them, along with water, as urine.

The kidneys perform this vital function by filtering the blood. Thekidneys have a very rich blood supply. The kidneys receive unfilteredblood directly from the heart through the abdominal aorta, whichbranches to the left and right renal arteries to serve the left andright kidneys, respectively. Filtered blood then returns by the left andright renal veins to the inferior vena cava and then the heart. Renalblood flow accounts for approximately one quarter of cardiac output.

In each kidney, the renal artery transports blood with waste productsinto the respective kidney. As the blood passes through the kidneys,waste products and unneeded water and electrolytes are collected andturned into urine. Filtered blood is returned to the heart by the renalvein. From the kidneys, the urine drains into the bladder down tubescalled the ureters (one for each kidney). Another tube called theurethra carries the urine from the bladder out of the body.

As FIGS. 2A, 2B, and 2C show, inside the kidney, the blood is filteredthrough very small networks of tubes called nephrons (best shown in FIG.2B). Each kidney has about 1 million nephrons. As FIG. 2B shows, eachnephron is made up of glomeruli, which are covered by sacs (calledBowman's capsules) and connected to renal tubules. Inside the nephrons,waste products in the blood move across from the bloodstream (thecapillaries) into the tubules. As the blood passes through the bloodvessels of the nephron, unwanted waste is taken away. Any chemicalsneeded by the body are kept or returned to the bloodstream by thenephrons.

About seventy-five percent of the constituents of crude urine and aboutsixty-six percent of the fluid are reabsorbed in the first portion ofthe renal tubules, called the proximal renal tubules (see FIG. 2B).Readsorption is completed in the loop of Henle and in the last portionof the renal tubules, called the distal convoluted tubules, producingurine. The urine is carried by collecting tubule of the nephron to theureter. In this way, the kidneys help to regulate the levels ofchemicals in the blood such as sodium and potassium, and keep the bodyhealthy.

2. The Physiologic Regulation Functions

Because the kidneys are poised to sense plasma concentrations of ionssuch as sodium, potassium, hydrogen, oxygen, and compounds such as aminoacids, creatinine, bicarbonate, and glucose in the blood, they areimportant regulators of blood pressure; glucose metabolism, anderythropoiesis (the process by which red blood cells are produced).

The kidney is one of the major organs involved in whole-bodyhomeostasis. Besides filtering the blood, the kidneys perform acid-basebalance, regulation of electrolyte concentrations, control of bloodvolume, and regulation of blood pressure. The kidneys accomplish theseshomeostatic functions independently and through coordination with otherorgans, particularly those of the endocrine system.

The kidneys produce and secrete three important hormones: (1)erythropoietin (EPO), which tells the bone marrow to make red bloodcells; (2) renin, which regulates blood pressure; and (3) calcitriol (aform of Vitamin D), which helps the intestine to absorb calcium from thediet, and so helps to keep the bones healthy.

Renin is produced by a densely packed areas of specialized cells, calledmacula densa, in the region of juxtaglomerular cells, which line thewall of the distal convoluted tubule (DCT) (see FIG. 2C). The cells ofthe macula densa are sensitive to the ionic content and water volume ofthe fluid in the DCT, producing molecular signals that promote reninsecretion by other cells of the juxtaglomerular cell region. As will bedescribed in greater detail later, the release of renin is an essentialcomponent of the renin-angiotensin-aldosterone system (RAAS), whichregulates blood pressure and volume.

(i) The Renin-Angiotensin System

The renin-angiotensin system (RAS) or the renin-angiotensin-aldosteronesystem (RAAS) is a hormone system that regulates blood pressure andwater (fluid) balance.

When blood pressure is low, the kidneys secrete renin, as explainedabove. Renin stimulates the production of angiotensin. Angiotensin andits derivatives cause blood vessels to constrict, resulting in increasedblood pressure. Angiotensin also stimulates the secretion of the hormonealdosterone from the adrenal cortex. Aldosterone causes the tubules ofthe kidneys to retain sodium and water. This increases the volume offluid in the body, which also increases blood pressure.

If the renin-angiotensin-aldosterone system is too active, bloodpressure will be too high. There are many drugs which interruptdifferent steps in this system to lower blood pressure. These drugs areone of the main ways to control high blood pressure (hypertension),heart failure, kidney failure, and harmful effects of diabetes.

B. The Sympathetic Nervous System

The Sympathetic Nervous System (SNS) is a branch of the autonomicnervous system along with the enteric nervous system and parasympatheticnervous system. It is always active at a basal level (called sympathetictone) and becomes more active during times of stress. Like other partsof the nervous system, the sympathetic nervous system operates through aseries of interconnected neurons. Sympathetic neurons are frequentlyconsidered part of the peripheral nervous system (PNS), although manylie within the central nervous system (CNS). Sympathetic neurons of thespinal cord (which is part of the CNS) communicate with peripheralsympathetic neurons via a series of sympathetic ganglia. Within theganglia, spinal cord sympathetic neurons join peripheral sympatheticneurons through synapses. Spinal cord sympathetic neurons are thereforecalled presynaptic (or preganglionic) neurons, while peripheralsympathetic neurons are called postsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation can elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to things as diverse as pupildiameter, gut motility, and urinary output. This response is also knownas sympatho-adrenal response of the body, as the preganglionicsympathetic fibers that end in the adrenal medulla (but also all othersympathetic fibers) secrete acetylcholine, which activates the secretionof adrenaline (epinephrine) and to a lesser extent noradrenaline(norepinephrine). Therefore, this response that acts primarily on thecardiovascular system is mediated directly via impulses transmittedthrough the sympathetic nervous system and indirectly via catecholaminessecreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 3A, the SNS provides a network of nerves that allowsthe brain to communicate with the body. Sympathetic nerves originateinside the vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to the either the paravertebral(which lie near the vertebral column) or prevertebral (which lie nearthe aortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons must travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia. The cell that sends its fiberis called a preganglionic cell, while the cell whose fiber leaves theganglion is called a postganglionic cell. As mentioned previously, thepreganglionic cells of the SNS are located between the first thoracicsegment and third lumbar segments of the spinal cord. Postganglioniccells have their cell bodies in the ganglia and send their axons totarget organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 3B shows, the kidney is innervated by the renal plexus (RP),which is intimately associated with the renal artery. The renal plexus(RP) is an autonomic plexus that surrounds the renal artery and isembedded within the adventitia of the renal artery. The renal plexusextends along the renal artery until it arrives at the substance of thekidney. Fibers contributing to the renal plexus arise from the celiacganglion, the superior mesenteric ganglion, the aorticorenal ganglionand the aortic plexus. The renal plexus (RP), also referred to as therenal nerve, is predominantly comprised of sympathetic components. Thereis no (or at least very minimum) parasympathetic innervation of thekidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus (RP) and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages can trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system canaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. As described above, pharmaceutical management of therenin-angiotensin-aldosterone system has been the longstanding forreducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate and left ventricular ejection fraction. Thesefindings support the notion that treatment regimens that are designed toreduce renal sympathetic stimulation have the potential to improvesurvival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renal diseaseplasma levels of norepinephrine above the median have been demonstratedto be predictive for both all cause death and death from cardiovasculardisease. This is also true for patients suffering from diabetic orcontrast nephropathy. There is compelling evidence that suggests thatsensory afferent signals originating from the diseased kidneys are majorcontributors to initiate and sustain elevated central sympatheticoutflow in this patient group, which facilitates the occurrence of thewell known adverse consequences of chronic sympathetic overactivity suchas hypertension, left ventricular hypertrophy, ventricular arrhythmiasand sudden cardiac death.

Several forms of “renal injury” can induce activation of sensoryafferent signals. For example, renal ischemia, reduction in strokevolume or renal blood flow, or an abundance of adenosine enzyme maytrigger activation of afferent neural communication. As shown in FIGS.3C and 3D, this afferent communication might be from the kidney to thebrain or might be from one kidney to the other kidney. These afferentsignals are centrally integrated and result in increased sympatheticoutflow. This sympathetic drive is directed towards the kidneys, therebyactivating the RAAS and inducing increased renin secretion, sodiumretention, volume retention and vasoconstriction. Central sympatheticoveractivity also impacts other organs and bodily structures innervatedby sympathetic nerves such as the heart and the peripheral vasculature,resulting in the described adverse effects of sympathetic activation,several aspects of which also contribute to the rise in blood pressure.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na+) reabsorption and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects, and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Intra-renal pathology, such asischemia, hypoxia or other injury, results in an increase in renalafferent activity. Renal sensory afferent nerve activity directlyinfluences sympathetic outflow to the kidneys and other highlyinnervated organs involved in cardiovascular control such as the heartand peripheral blood vessels, by modulating posterior hypothalamicactivity.

The physiology therefore suggests that (i) denervation of efferentsympathetic nerves will reduce inappropriate renin release, saltretention, and reduction of renal blood flow, and that (ii) denervationof afferent sensory nerves will reduce the systemic contribution tohypertension through its direct effect on the posterior hypothalamus aswell as the contralateral kidney. In addition to the central hypotensiveeffects of afferent renal denervation, a desirable reduction of centralsympathetic outflow to various other sympathetically innervated organssuch as the heart and the vasculature is anticipated.

C. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, diabetes, left ventricularhypertrophy, chronic and end stage renal disease, inappropriate fluidretention in heart failure, cardio-renal syndrome and sudden death.Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation can alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 3A. For example, a reductionin central sympathetic drive may reduce the insulin resistance thatafflicts people with metabolic syndrome and Type II diabetics.Additionally, patients with osteoporosis are also sympatheticallyactivated and might also benefit from the downregulation of sympatheticdrive that accompanies renal denervation.

D. Achieving Intravascular Access to the Renal Artery

As FIG. 4A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries(as FIG. 1A also shows). Below the renal arteries, the aorta bifurcatesat the left and right iliac arteries. The left and right iliac arteriesdescend, respectively, through the left and right legs and join the leftand right femoral arteries.

As FIG. 4B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins (as FIG. 1A also shows). Above the renal veins, the inferior venacava ascends to convey blood into the right atrium of the heart. Fromthe right atrium, the blood is pumped through the right ventricle intothe lungs, where it is oxygenated. From the lungs, the oxygenation bloodis conveyed into the left atrium. From the left atrium, the oxygenatedblood is conveyed by the left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery can beexposed and cannulated at the base of the femoral triangle, justinferior to the midpoint of the inguinal ligament. A catheter can beinserted through this access site, percutaneously into the femoralartery and passed into the iliac artery and aorta, into either the leftor right renal artery. This comprises an intravascular path that offersminimally invasive access to a respective renal artery and/or otherrenal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. Catheterization ofeither the radial, brachial, or axillary artery may be utilized inselect cases. Catheters introduced via these access points may be passedthrough the subclavian artery on the left side (or via the subclavianand brachiocephalic arteries on the right side), through the aorticarch, down the descending aorta and into the renal arteries usingstandard angiographic technique.

II. Apparatus, Systems and Methods for Achieving Intravascular,Thermally Induced Renal Neuromodulation

A. Overview

FIG. 5 shows a system 10 for thermally inducing neuromodulation of aleft and/or right renal plexus (RP) through intravascular access.

As just described, the left and/or right renal plexus (RP) surrounds therespective left and/or right renal artery. The renal plexus (RP) extendsin intimate association with the respective renal artery into thesubstance of the kidney. The system thermally induces neuromodulation ofa renal plexus (RP) by intravascular access into the respective left orright renal artery.

The system 10 includes an intravascular treatment device 12. Thetreatment device 12 provides access to the renal plexus (RP) through anintravascular path 14 that leads to a respective renal artery, as FIG.6A shows.

As FIG. 5 shows, the treatment device 12 includes an elongated shaft 16having a proximal end region 18 and a distal end region 20.

The proximal end region 18 of the elongated shaft 16 includes a handle22. The handle 22 is sized and configured to be securely held andmanipulated by a caregiver (not shown) outside an intravascular path 14(this is shown in FIG. 6A). By manipulating the handle 22 from outsidethe intravascular path 14, the caregiver can advance the elongated shaft16 through the tortuous intravascular path 14. Image guidance, e.g., CT,radiographic, or another suitable guidance modality, or combinationsthereof, can be used to aid the caregiver's manipulation.

As shown in FIG. 6B, the distal end region 20 of the elongated shaft 16can flex in a substantial fashion to gain entrance into a respectiveleft/right renal artery by manipulation of the elongated shaft 16. Asshown in FIGS. 19A and 19B, the distal end region 20 of the elongatedshaft 16 can gain entrance to the renal artery via passage within aguide catheter 94. The distal end region 20 of the elongated shaft 16carries at least one thermal element 24 (e.g., thermal heating element).The thermal heating element 24 is also specially sized and configuredfor manipulation and use within a renal artery.

As FIG. 6B shows (and as will be described in greater detail later),once entrance to a renal artery is gained, further manipulation of thedistal end region 20 and the thermal heating element 24 within therespective renal artery establishes proximity to and alignment betweenthe thermal heating element 24 and tissue along an interior wall of therespective renal artery. In some embodiments, manipulation of the distalend region 20 will also facilitate contact between the thermal heatingelement 24 and wall of the renal artery.

As will also be described in greater detail later, different sections ofthe elongated shaft 16 serve different mechanical functions when in use.The sections are thereby desirably differentiated in terms of theirsize, configuration, and mechanical properties for (i) percutaneousintroduction into a femoral artery through a small-diameter access site;(ii) atraumatic passage through the tortuous intravascular path 14through an iliac artery, into the aorta, and into a respectiveleft/right renal artery, including (iii) significant flexure near thejunction of the left/right renal arteries and aorta to gain entry intothe respective left or right renal artery; (iv) controlled translation,deflection, and/or rotation within the respective renal artery to attainproximity to and a desired alignment with an interior wall of therespective renal artery; and (v) the placement of a thermal heatingelement 24 into contact with tissue on the interior wall.

Referring back to FIG. 5, the system 10 also includes a thermalgenerator 26 (e.g., a thermal energy generator). Under the control ofthe caregiver or automated control algorithm 102 (as will be describedin greater detail later), the generator 26 generates a selected form andmagnitude of thermal energy. A cable 28 operatively attached to thehandle 22 electrically connects the thermal heating element 24 to thegenerator 26. At least one supply wire (not shown) passing along theelongated shaft 16 or through a lumen in the elongated shaft 16 from thehandle 22 to the thermal heating element 24 conveys the treatment energyto the thermal heating element 24. A foot pedal 100 is electricallyconnected to the generator 26 to allow the operator to initiate,terminate and, optionally, adjust various operational characteristics ofthe generator, including, power delivery. For systems that provide forthe delivery of a monopolar electric field via the thermal heatingelement 24, a neutral or dispersive electrode 38 can be electricallyconnected to the generator 26. Additionally, a sensor (not shown), suchas a temperature (e.g., thermocouple, thermistor, etc.) or impedancesensor, can be located proximate to or within the thermal heatingelement and connected to one or more of the supply wires. With twosupply wires, one wire could convey the energy to the thermal heatingelement and one wire could transmit the signal from the sensor.Alternatively, both wires could transmit energy to the thermal heatingelement.

Once proximity to, alignment with, and contact between the thermalheating element 24 and tissue are established within the respectiverenal artery (as FIG. 6B shows), the purposeful application of energyfrom the generator 26 to tissue by the thermal heating element 24induces one or more desired thermal heating effects on localized regionsof the renal artery and adjacent regions of the renal plexus (RP), whichlay intimately within or adjacent to the adventitia of the renal artery.The purposeful application of the thermal heating effects can achieveneuromodulation along all or a portion of the RP.

The thermal heating effects can include both thermal ablation andnon-ablative thermal alteration or damage (e.g., via sustained heatingand/or resistive heating). Desired thermal heating effects may includeraising the temperature of target neural fibers above a desiredthreshold to achieve non-ablative thermal alteration, or above a highertemperature to achieve ablative thermal alteration. For example, thetarget temperature can be above body temperature (e.g., approximately37° C.) but less than about 45° C. for non-ablative thermal alteration,or the target temperature can be about 45° C. or higher for the ablativethermal alteration.

Further details of special size, configuration, and mechanicalproperties of the elongated shaft 16 and the thermal heating element 24,as well as other aspects of the system 10 will now be described. Instill other embodiments, the system 10 may have a differentconfiguration and/or include different features. For example,multi-thermal heating element devices, such as multi-electrode basketsor other balloon expandable devices may be implemented tointravascularly deliver neuromodulatory treatment with or withoutcontact the vessel wall.

B. Size and Configuration of the Elongated Shaft for AchievingIntravascular Access to a Renal Artery

As explained above, intravascular access to an interior of a renalartery can be achieved through the femoral artery. As FIG. 6B shows, theelongated shaft 16 is specially sized and configured to accommodatepassage through this intravascular path 14, which leads from apercutaneous access site in the femoral artery to a targeted treatmentsite within a renal artery. In this way, the caregiver is able to orientthe thermal heating element 24 within the renal artery for its intendedpurpose.

For practical purposes, the maximum outer dimension (e.g., diameter) ofany section of the elongated shaft 16, including the thermal heatingelement 24 it carries, is dictated by the inner diameter of the guidecatheter through which the elongated shaft 16 is passed. Assuming, forexample, that an 8 French guide catheter (which has an inner diameter ofapproximately 0.091 inches) would likely be, from a clinicalperspective, the largest guide catheter used to access the renal artery,and allowing for a reasonable clearance tolerance between the thermalheating element 24 and the guide catheter, the maximum outer dimensioncan be realistically expressed as being less than or equal toapproximately 0.085 inches. However, use of a smaller 5 French guidecatheter 94 may require the use of smaller outer diameters along theelongated shaft 16. For example, a thermal heating element 24 that is tobe routed within a 5 French guide catheter would have an outer dimensionof no greater than 0.053 inches. In another example, a thermal heatingelement 24 that is to be routed within a 6 French guide catheter wouldhave an outer dimension of no great than 0.070 inches.

1. Proximal Force Transmitting Section

As FIG. 7A shows, the proximal end region 18 of the elongated shaft 16includes, coupled to the handle 22, a force transmitting section 30. Theforce transmitting section 30 is sized and configured to possessselected mechanical properties that accommodate physical passage throughand the transmission of forces within the intravascular path 14, as itleads from the accessed femoral artery (left or right), through therespective iliac branch artery and into the aorta, and in proximity tothe targeted renal artery (left or right). The mechanical properties ofthe force transmitting section 30 include at least a preferred effectivelength (expressed in inches or centimeters).

As FIG. 7A shows, the force transmitting section 30 includes a preferredeffective length L1. The preferred effective length L1 is a function ofthe anatomic distance within the intravascular path 14 between theaccess site and a location just proximate to the junction of the aortaand renal arteries. The preferred effective length L1 can be derivedfrom textbooks of human anatomy, augmented by a caregiver's knowledge ofthe targeted site generally or as derived from prior analysis of theparticular morphology of the targeted site. The preferred effectivelength L1 is also dependent on the length of the guide catheter that isused, if any. In a representative embodiment, for a normal human, thepreferred effective length L1 comprises about 30 cm to about 110 cm. Ifno guide catheter is used, then the preferred effective length L1comprises about 30 cm to about 35 cm. If a 55 cm length guide catheteris used, then the preferred effective length L1 comprises about 65 cm toabout 70 cm. If a 90 cm length guide catheter is used, then thepreferred effective length L1 comprises about 95 cm to about 105 cm.

The force transmitting section 30 also includes a preferred axialstiffness and a preferred torsional stiffness. The preferred axialstiffness expresses the capability of the force transmitting section 30to be advanced or withdrawn along the length of the intravascular path14 without buckling or substantial deformation. Since some axialdeformation is necessary for the force transmitting section 30 tonavigate the tortuous intravascular path 14 without providing too muchresistance, the preferred axial stiffness of the force transmittingsection should also provide this capability. The preferred torsionalstiffness expresses the capability of the force transmitting section 30to rotate the elongated shaft 16 about its longitudinal axis along itslength without kinking or permanent deformation. As will be described ingreater detail later, the ability to advance and retract, as well asrotate, the distal end region 20 of the elongated shaft 16 within therespective renal artery is desirable.

The desired magnitude of axial stiffness and rotational stiffness forthe force transmitting section 30 can be obtained by selection ofconstituent material or materials to provide a desired elastic modulus(expressed in terms, e.g., of a Young's Modulus (E)) indicative of axialand torsional stiffnesses, as well as selecting the construct andconfiguration of the force transmitted section in terms of, e.g., itsinterior diameter, outer diameter, wall thickness, and structuralfeatures, including cross-sectional dimensions and geometry.Representative examples are described in greater detail below.

2. Proximal Flexure Zone

As FIGS. 7A and 7B show, the distal end region 20 of the elongated shaft16 is coupled to the force transmitting section 30. The length L1 of theforce transmitting section 30 generally serves to bring the distal endregion 20 into the vicinity of the junction of the respective renalartery and aorta (as FIG. 6B shows). The axial stiffness and torsionalstiffness of the force transmitting region transfer axial and rotationforces from the handle 22 to the distal end region 20, as will bedescribed in greater detail later.

As shown in FIG. 7B, the distal end region 20 includes a first orproximal flexure zone 32 proximate to the force transmitting section 30.The proximal flexure zone 32 is sized and configured to have mechanicalproperties that accommodate significant flexure or bending at aprescribed preferred access angle α1 and provide for the transmission oftorque during rotation, without fracture, collapse, substantialdistortion, or significant twisting of the elongated shaft 16. Theproximal flexure zone 32 should accommodate flexure sufficient for thedistal end region 20 to advance via a guide catheter into the renalartery without substantially straightening out the guide catheter.

Angle α1 is defined by the angular deviation that the treatment device12 must navigate to transition from the aorta (along which the forcetransmitting section 30 is aligned) and the targeted renal artery (alongwhich the distal end region 20 is aligned) (this is also shown in FIG.6B). This is the angle that the proximal flexure zone 32 mustapproximate to align the distal end region 20 of the elongated shaft 16with the targeted renal artery, while the force transmitting section 30of the elongated shaft 16 remains aligned with the native axis of theaorta (as FIG. 6B shows). The more tortuous a vessel, the greater bendthe proximal flexure zone 32 will need to make for the distal end regionof the treatment device to access the renal artery and the smaller theangle α1.

The proximal flexure zone 32 is sized and configured to possessmechanical properties that accommodate significant, abrupt flexure orbending at the access angle α1 near the junction of the aorta and therenal artery. Due to its size, configuration, and mechanical properties,the proximal flexure zone 32 must resolve these flexure or bendingforces without fracture, collapse, distortion, or significant twisting.The resolution of these flexure or bending forces by the proximalflexure zone 32 makes it possible for the distal end region 20 of theelongated shaft 16 to gain entry along the intravascular path 14 into atargeted left or right renal artery.

The proximal flexure zone 32 is sized and configured in length L2 to beless than length L1 (see FIG. 7A). That is because the distance betweenthe femoral access site and the junction of the aorta and renal artery(typically approximating about 40 cm to about 55 cm) is generallygreater than the length of a renal artery between the aorta and the mostdistal treatment site along the length of the renal artery, which istypically about 4 cm to about 6 cm. The preferred effective length L2can be derived from textbooks of human anatomy, augmented with acaregiver's knowledge of the site generally or as derived from prioranalysis of the particular morphology of the targeted site.

Desirably, the length L2 is selected to make it possible to rest aportion of the proximal flexure zone 32 partially in the aorta at ornear the length L1, as well as rest the remaining portion of theproximal flexure zone 32 partially within the renal artery (as FIG. 6Bshows). In this way, the proximal flexure zone 32 defines a transitionalbend that is supported and stable within the vasculature.

As will be described in greater detail later, and as shown in FIG. 6B,the length L2 of the proximal flexure zone 32 desirably does not extendthe full length of the targeted length of the renal artery. That isbecause the distal end region 20 of the elongated shaft 16 desirablyincludes one or more additional flexure zones, distal to the proximalflexure zone 32 (toward the substance of the kidney), to accommodateother different functions important to the therapeutic objectives of thetreatment device 12. As will be described later, the ability to transmittorque through the proximal flexure zone 32 makes it possible to rotatethe thermal heating device to properly position the thermal heatingelement within the renal artery for treatment.

In terms of axial and torsional stiffness, the mechanical properties ofproximal flexure zone 32 can and desirably do differ from the mechanicalproperties of the force transmitting section 30. This is because theproximal flexure zone 32 and the force transmitting region servedifferent functions while in use. Alternatively, the mechanicalproperties of proximal flexure zone 32 and force transmitting section 30can be similar.

The force transmitting section 30 serves in use to transmit axial loadand torque over a relatively long length (L1) within the vascularpathway. In contrast, the proximal flexure zone 32 needs to transmitaxial load and torque over a lesser length L2 proximate to or within arespective renal artery. Importantly, the proximal flexure zone 32 mustabruptly conform to an access angle α1 near the junction of the aortaand the respective renal artery, without fracture, collapse, substantialdistortion, or significant twisting. This is a function that the forcetransmitting zone need not perform. Accordingly, the proximal flexurezone 32 is sized and configured to be less stiff and to possess greaterflexibility than the force transmitting section 30.

The desired magnitude of axial stiffness, rotational stiffness, andflexibility for the proximal flexure zone 32 can be obtained byselection of constituent material or materials to provide a desiredelastic modulus (expressed, e.g., in terms of a Young's Modulus (E))indicative of flexibility, as well as selecting the construct andconfiguration of the force transmitting section, e.g., in terms of itsinterior diameter, outer diameter, wall thickness, and structuralfeatures, including cross-sectional dimensions and geometry.Representative examples will be described in greater detail later.

Although it is desirable that the force transmitting section 30 and theproximal flexure zone 32 have stiffness and flexibility properties thatare unique to their respective functions, it is possible that the forcetransmitting section 30 and the proximal flexure zone 32 comprise thesame materials, size and geometric configuration such that the forcetransmitting section 30 and the proximal flexure zone 32 constitute thesame section.

3. Intermediate Flexure Zone

As shown in FIGS. 7A, 7B, and 7C, the distal end region 20 of theelongated shaft 16 may also include, distal to the proximal flexure zone32, a second or intermediate flexure zone 34. The thermal heatingelement 24 may be supported by the intermediate flexure zone 34.

The intermediate flexure zone 34 is sized, configured, and has themechanical properties that accommodate additional flexure or bending,independent of the proximal flexure zone 32, at a preferred contactangle α2, without fracture, collapse, substantial distortion, orsignificant twisting. The intermediate flexure zone 34 should alsoaccommodate flexure sufficient for the distal end region 20 to advancevia a guide catheter into the renal artery without straightening out theguide catheter.

The preferred contact angle α2 is defined by the angle through which thethermal heating element 24 can be radially deflected within the renalartery to establish contact between the thermal heating element 24 andan inner wall of the respective renal artery (as FIG. 6B shows). Thesize of the contact angle α2 and the intermediate flexure zone length L3are based on the native inside diameter of the respective renal arterywhere the thermal heating element 24 rests, which may vary between about2 mm and about 10 mm. It is most common for the diameter of the renalartery to vary between about 3 mm and about 7 mm.

The intermediate flexure zone 34 extends from the proximal flexure zone32 for a length L3 into the targeted renal artery (see FIG. 6B).Desirably, the length L3 is selected, taking into account the length L2of the proximal flexure zone 32 that extends into the renal artery, aswell as the anatomy of the respective renal artery, to actively placethe thermal heating element 24 (carried at the end of the distal endregion 20) at or near the targeted treatment site (as FIG. 6B shows).The length L3 can be derived, taking the length L2 into account, fromtextbooks of human anatomy, together with a caregiver's knowledge of thesite generally or as derived from prior analysis of the particularmorphology of the targeted site. In a representative embodiment, L2 isabout 9 cm and L3 is about 5 mm to about 15 mm. In certain embodiments,particularly for treatments in relatively long blood vessels, L3 can beas long as about 20 mm. In another representative embodiment, and asdescribed later in greater detail, L3 is about 12.5 mm.

As FIG. 7A shows, the intermediate flexure zone 34 is desirably sizedand configured in length L3 to be less than length L2. This is because,in terms of length, the distance required for actively deflecting thethermal heating element 24 into contact with a wall of the renal arteryis significantly less than the distance required for bending theelongated shaft 16 to gain access from the aorta into the renal artery.Thus, the length of the renal artery is occupied in large part by theintermediate flexure zone 34 and not as much by the proximal flexurezone 32.

As FIG. 7C shows, having proximal and intermediate flexure zones 32 and34, the distal end region 20 of the elongated shaft 16 can, in use, beplaced into a complex, multi-bend structure 36. The complex, multi-bendstructure 36 comprises one deflection region at the access angle α1 overa length L2 (the proximal flexure zone 32) and a second deflectionregion at the contact angle α2 over a length L3 (the intermediateflexure zone 34). In the complex, multi-bend, both L2 and L3 and angleα1 and angle α2 can differ. This is because the angle α1 and length L2are specially sized and configured to gain access from an aorta into arespective renal artery through a femoral artery access point, and theangle α2 and length L3 are specially sized and configured to align athermal heating element 24 with an interior wall inside the renalartery.

In the illustrated embodiment (see, e.g., FIG. 7C), the intermediateflexure zone 34 is sized and configured to allow a caregiver to remotelydeflect the intermediate flexure zone 34 within the renal artery, toradially position the thermal heating element 24 into contact with aninner wall of the renal artery.

In the illustrated embodiment, a control mechanism is coupled to theintermediate flexure zone 34. The control mechanism includes a controlwire 40 attached to the distal end of the intermediate flexure zone 34(a representative embodiment is shown in FIGS. 12B and 12C and will bedescribed in greater detail later). The control wire 40 is passedproximally through the elongated shaft 16 and coupled to an actuator 42on the handle 22. Operation of the actuator 42 (e.g., by the caregiverpulling proximally on or pushing forward the actuator 42) pulls thecontrol wire 40 back to apply a compressive and bending force to theintermediate flexure zone 34 (as FIGS. 7C and 12C show) resulting inbending. The compressive force in combination with the optionaldirectionally biased stiffness (described further below) of theintermediate flexure zone 34 deflects the intermediate flexure zone 34and, thereby, radially moves the thermal heating element 24 toward aninterior wall of the renal artery (as FIG. 6B shows).

Desirably, as will be described in greater detail later, the distal endregion 20 of the elongated shaft 16 can be sized and configured to varythe stiffness of the intermediate flexure zone 34 about itscircumference. The variable circumferential stiffness impartspreferential and directional bending to the intermediate flexure zone 34(i.e., directionally biased stiffness). In response to operation of theactuator 42, the intermediate flexure zone 34 may be configured to bendin a single preferential direction. Representative embodimentsexemplifying this feature will be described in greater detail later.

The compressive and bending force and resulting directional bending fromthe deflection of the intermediate flexure zone 34 has the consequenceof altering the axial stiffness of the intermediate flexure zone. Theactuation of the control wire 40 serves to increase the axial stiffnessof the intermediate flexure zone.

In terms of axial and torsional stiffnesses, the mechanical propertiesof intermediate flexure zone 34 can and desirably do differ from themechanical properties of the proximal flexure zone 32. This is becausethe proximal flexure zone 32 and the intermediate flexure zone 34 servedifferent functions while in use.

The proximal flexure zone 32 transmits axial load and torque over alonger length (L2) than the intermediate flexure zone 34 (L3).Importantly, the intermediate flexure zone 34 is also sized andconfigured to be deflected remotely within the renal artery by thecaregiver. In this arrangement, less resistance to deflection isdesirable. This is a function that the proximal flexure zone 32 need notperform. Accordingly, the intermediate flexure zone 34 is desirablysized and configured to be less stiff (when the control wire 40 is notactuated) and, importantly, to possess greater flexibility than theproximal flexure zone 32 in at least one plane of motion.

Still, because the intermediate flexure zone 34, being distal to theproximal flexure zone 32, precedes the proximal flexure zone 32 throughthe access angle access angle α1, the intermediate flexure zone 34 alsoincludes mechanical properties that accommodate its flexure or bendingat the preferred access angle α1, without fracture, collapse,substantial distortion, or significant twisting of the elongated shaft16.

The desired magnitude of axial stiffness, rotational stiffness, andflexibility for the intermediate flexure zone 34 can be obtained byselection of constituent material or materials to provide a desiredelastic modulus (expressed, e.g., in terms of a Young's Modulus (E))indicative of flexibility, as well as by selecting the construct andconfiguration of the intermediate flexure zone 34, e.g., in terms of itsinterior diameter, outer diameter, wall thickness, and structuralfeatures, including cross-sectional dimensions and geometry.Representative examples will be described in greater detail later. Axialstiffness, torsional stiffness, and flexibility are properties that canbe measured and characterized in conventional ways.

As before described, both the proximal and intermediate flexure zones 32and 34 desirably include the mechanical properties of axial stiffnesssufficient to transmit to the thermal heating element 24 an axiallocating force. By pulling back on the handle 22, axial forces aretransmitted by the force transmitting section 30 and the proximal andintermediate flexure zones 32 and 34 to retract the thermal heatingelement 24 in a proximal direction (away from the kidney) within therenal artery. Likewise, by pushing forward on the handle 22, axialforces are transmitted by the force transmitting section 30 and theproximal and intermediate flexure zones 32 and 34 to advance the thermalheating element 24 in a distal direction (toward the kidney) within therenal artery. Thus, proximal retraction of the distal end region 20 andthermal heating element 24 within the renal artery can be accomplishedby the caregiver by manipulating the handle 22 or shaft from outside theintravascular path 14.

As before described, both the proximal and intermediate flexure zones 32and 34 also desirably include torsional strength properties that willallow the transmission of sufficient rotational torque to rotate thedistal end region 20 of the treatment device 12 such that the thermalheating element 24 is alongside the circumference of the blood vesselwall when the intermediate flexure zone 34 is deflected. By pulling orpushing on the actuator to deflect the thermal heating element 24 suchthat it achieves vessel wall contact, and then rotating the forcetransmitting section 30 and, with it, the first and intermediate flexurezones 32 and 34, the thermal heating element 24 can be rotated in acircumferential path within the renal artery. As described later, thisrotating feature enables the clinical operator to maintain vessel wallcontact as the thermal heating element 24 is being relocated to anothertreatment site. By maintaining wall contact in between treatments, theclinical operator is able to achieve wall contact in subsequenttreatments with higher certainty in orientations with poorvisualization.

4. Distal Flexure Zone

As shown in FIGS. 7A, 7B, 7C, and 7D, the distal end region 20 of theelongated shaft 16 can also include, distal to the intermediate flexurezone 34, a third or distal flexure zone 44. In this arrangement, thelength L3 of the intermediate flexure zone 34 may be shortened by alength L4, which comprises the length of the distal flexure zone 44. Inthis arrangement, the thermal heating element 24 is carried at the endof the distal flexure zone 44. In effect the distal flexure zone 44buttresses the thermal heating element 24 at the distal end of distalend region 20.

As FIG. 7D shows, the distal flexure zone 44 is sized, configured, andhas the mechanical properties that accommodate additional flexure orbending, independent of the proximal flexure zone 32 and theintermediate flexure zone 34, at a preferred treatment angle α3. Thedistal flexure zone 44 should also accommodate flexure sufficient forthe distal end region 20 to advance via a guide catheter into the renalartery without straightening out the guide catheter or causing injury tothe blood vessel. The treatment angle α3 provides for significantflexure about the axis of the distal end region 20 (a representativeembodiment is shown in FIG. 15C). Not under the direct control of thephysician, flexure at the distal flexure zone occurs in response tocontact between the thermal heating element 24 and wall tissueoccasioned by the radial deflection of the thermal heating element 24 atthe intermediate flexure zone 34 (see FIG. 6B). Passive deflection ofthe distal flexure zone provides the clinical operator with visualfeedback via fluoroscopy or other angiographic guidance of vessel wallcontact. Additionally, the distal flexure zone desirably orients theregion of tissue contact along a side of the thermal heating element 24,thereby increasing the area of contact. The distal flexure zone 44 alsobiases the thermal heating element 24 against tissue, therebystabilizing the thermal heating element 24.

The function of the distal flexure zone 44 provides additional benefitsto the therapy. As actuation of the control wire 40 increases the axialstiffness of the intermediate flexure zone 34, the distal flexure zoneeffectively reduces the contact force between the thermal heatingelement 24 and the vessel wall. By relieving or reducing this contactforce, the distal flexure zone minimizes the chance of mechanical injuryto the vessel wall and avoids excessive contact between the thermalheating element and vessel wall (see discussion of active surface area).

As FIG. 7A shows, the distal flexure zone 44 is desirably sized andconfigured in length L4 to be less than length L3. This is because, interms of length, the distance required for orienting and stabilizing thethermal heating element 24 in contact with a wall of the renal artery issignificantly less than the distance required for radially deflectingthe thermal heating element 24 within the renal artery. In someembodiments, length L4 can be as long as about 1 cm. In otherembodiments, the length L4 is from about 2 mm to about 5 mm. In apreferred embodiment, the length L4 is about 5 mm. In other embodiments,the length L4 is about 2 mm.

The mechanical properties of the distal flexure zone 44 and theintermediate flexure zone 34 in terms of axial stiffness, torsionalstiffness, and flexibility can be comparable. However, the distalflexure zone 44 can be sized and configured to be less stiff and,importantly, to possess greater flexibility than the intermediateflexure zone 34.

In the embodiment just described (and as shown in FIG. 7D), the distalend region 20 may comprise a proximal flexure zone 32, a intermediateflexure zone 34, and a distal flexure zone 44. The proximal,intermediate and distal flexure zones function independent from eachother, so that the distal end region 20 of the elongated shaft 16 can,in use, be placed into a more compound, complex, multi-bend structure36. The compound, complex, multi-bend structure 36 comprises a proximaldeflection region at the access angle α1 over a length L2 (the proximalflexure zone 32); an intermediate deflection region at the contact angleα2 over a length L3 (the intermediate flexure zone 34); and a distaldeflection region at the treatment angle α3 over a length L4 (the distalflexure zone 44). In the compound, complex, multi-bend structure 36, alllengths L2, L3, and L3 and all angles α1, α2, and α3 can differ. This isbecause the angle α1 and length L2 are specially sized and configured togain access from an aorta into a respective renal artery through afemoral artery access point; the angle α2 and length L3 are speciallysized and configured to align a thermal heating element 24 element withan interior wall inside the renal artery; and the angle α3 and length L4are specially sized and configured to optimize surface contact betweentissue and the thermal heating element/heat transfer element.

C. Size and Configuration of the Thermal Heating Element for AchievingNeuromodulation in a Renal Artery

As described in co-pending patent application Ser. No. 11/599,890 filedNov. 14, 2006, which is incorporated herein by reference in itsentirety, it is desirable to create multiple focal lesions that arecircumferentially spaced along the longitudinal axis of the renalartery. This treatment approach avoids the creation of a full-circlelesion, thereby mitigating and reducing the risk of vessel stenosis,while still providing the opportunity to circumferentially treat therenal plexus, which is distributed about the renal artery. It isdesirable for each lesion to cover at least 10% of the vesselcircumference to increase the probability of affecting the renal plexus.However, it is important that each lesion not be too large (e.g., >60%of vessel circumference) lest the risk of a stenotic effect increases(or other undesirable healing responses such as thrombus formation orcollateral damage). It is also important that each lesion besufficiently deep to penetrate into and beyond the adventitia to therebyaffect the renal plexus.

As described (and as FIG. 8A shows), the thermal heating element 24 issized and configured, in use, to contact an internal wall of the renalartery. In the illustrated embodiment (see FIG. 8A), the thermal heatingelement 24 takes the form of an electrode 46 sized and configured toapply an electrical field comprising radiofrequency (RF) energy from thegenerator 26 to a vessel wall. In the illustrated embodiment, theelectrode 46 is operated in a monopolar or unipolar mode. In thisarrangement, a return path for the applied RF electric field isestablished, e.g., by an external dispersive electrode (not shown), alsocalled an indifferent electrode or neutral electrode. The monopolarapplication of RF electric field energy serves to ohmically orresistively heat tissue in the vicinity of the electrode 46. Theapplication of the RF electrical field thermally injures tissue. Thetreatment objective is to thermally induce neuromodulation (e.g.,necrosis, thermal alteration or ablation) in the targeted neural fibers.The thermal injury forms a lesion in the vessel wall, which is shown,e.g., in FIG. 9B.

The active surface area of contact (ASA) between the thermal heatingelement 24 or electrode 46 and the vessel wall has great bearing on theefficiency and control of the transfer of a thermal energy field acrossthe vessel wall to thermally affect targeted neural fibers in the renalplexus (RP). The active surface area of the thermal heating element 24and electrode 46 is defined as the energy transmitting area of theelement 24 or electrode 46 that can be placed in intimate contactagainst tissue. Too much contact between the thermal heating element andthe vessel wall may create unduly high temperatures at or around theinterface between the tissue and the thermal heating element, therebycreating excessive heat generation at this interface. This excessiveheat can create a lesion that is circumferentially too large. This canalso lead to undesirable thermal damage at the vessel wall. In additionto potentially causing stenotic injury, this undesirable thermal damagecan cause tissue desiccation (i.e., dehydration) which reduces thethermal conductivity of the tissue, thereby potentially creating alesion that is too shallow to reach the neural fibers. Too littlecontact between the thermal heating element and the vessel wall mayresult in superficial heating of the vessel wall, thereby creating alesion that is too small (e.g., <10% of vessel circumference) and/or tooshallow.

While the active surface area (ASA) of the thermal heating element 24and electrode 46 is important to creating lesions of desirable size anddepth, the ratio between the active surface area (ASA) and total surfacearea (TSA) of the thermal heating element 24 and electrode 46 is alsoimportant. The ASA to TSA ratio influences lesion formation in two ways:(1) the degree of resistive heating via the electric field, and (2) theeffects of blood flow or other convective cooling elements such asinjected saline. As discussed above, the RF electric field causes lesionformation via resistive heating of tissue exposed to the electric field.The higher the ASA to TSA ratio (i.e., the greater the contact betweenthe electrode and tissue), the greater the resistive heating. Asdiscussed in greater detail below, the flow of blood over the exposedportion of the electrode (TSA-ASA) provides conductive and convectivecooling of the electrode, thereby carrying excess thermal energy awayfrom the interface between the vessel wall and electrode. If the ratioof ASA to TSA is too high (e.g., 50%), resistive heating of the tissuecan be too aggressive and not enough excess thermal energy is beingcarried away, resulting in excessive heat generation and increasedpotential for stenotic injury, thrombus formation and undesirable lesionsize. If the ratio of ASA to TSA is too low (e.g., 10%), then there istoo little resistive heating of tissue, thereby resulting in superficialheating and smaller and shallower lesions.

Various size constraints for the thermal heating element 24 may beimposed for clinical reasons by the maximum desired dimensions of theguide catheter as well as by the size and anatomy of the renal arteryitself. Typically, the maximum outer diameter (or cross-sectionaldimension for non-circular cross-section) of the electrode 46 comprisesthe largest diameter encountered along the length of the elongated shaft16 distal to the handle 22. Thus, the outer diameters of the forcetransmitting section 30 and proximal, intermediate and distal flexurezones 32, 34, and 44 are equal to or (desirably) less than the maximumouter diameter of the electrode 46.

In a representative embodiment shown in FIG. 8A, the electrode 46 takesthe form of a right circular cylinder, possessing a length L5 that isgreater than its diameter. The electrode 46 further desirably includes adistal region that is rounded to form an atraumatic end surface 48. Inthe representative embodiment shown in FIG. 8B, the electrode 46 isspherical in shape. The spherical shape, too, presents an atraumaticsurface to the tissue interface.

As shown in FIGS. 8A and 8B, the angle α3 and length L4 of the distalflexure zone 44 are specially sized and configured, given the TSA of therespective electrode, to optimize an active surface area of contactbetween tissue and the respective electrode 46 (ASA). The angle α3 andthe length L4 of the distal flexure zone 44 make it possible todesirably lay at least a side quadrant 50 of the electrode 46 againsttissue (see FIG. 8C). The active surface area of the electrode 46contacting tissue (ASA) can therefore be expressed ASA≧0.25 TSA andASA≦0.50 TSA.

The above ASA-TSA relationship applies to the power delivery algorithmdescribed in co-pending patent application Ser. No. 12/147,154, filedJun. 26, 2008, which is incorporated herein by reference in itsentirety. An ASA to TSA ratio of over 50% may be effective with areduced power delivery profile. Alternatively, a higher ASA to TSA ratiocan be compensated for by increasing the convective cooling of theelectrode that is exposed to blood flow. As discussed further below,this could be achieved by injecting cooling fluids such as chilledsaline over the electrode and into the blood stream.

The stiffnesses of each of the intermediate and distal flexure zones 34and 44 are also selected to apply via the electrode a stabilizing forcethat positions the electrode 46 in substantially secure contact with thevessel wall tissue. This stabilizing force also influences the amount ofwall contact achieved by the thermal heating element (i.e., the ASA toTSA ratio). With greater stabilizing force, the thermal heating elementhas more wall contact and with less stabilizing force, less wall contactis achieved. Additional advantages of the stabilizing force include, (1)softening the contact force between the distal end 20 and vessel wall tominimize risk of mechanical injury to vessel wall, (2) consistentpositioning of the electrode 46 flat against the vessel wall, and (3)stabilizing the electrode 46 against the vessel wall. The stabilizingforce also allows the electrode to return to a neutral position afterthe electrode is removed from contact with the wall.

As previously discussed, for clinical reasons, the maximum outerdiameter (or cross-sectional dimension) of the electrode 46 isconstrained by the maximum inner diameter of the guide catheter throughwhich the elongated shaft 16 is to be passed through the intravascularpath 14. Assuming that an 8 French guide catheter 94 (which has an innerdiameter of approximately 0.091 inches) is, from a clinical perspective,the largest desired catheter to be used to access the renal artery, andallowing for a reasonable clearance tolerances between the electrode 46and the guide catheter, the maximum diameter of the electrode 46 isconstrained to about 0.085 inches. In the event a 6 French guidecatheter is used instead of an 8 French guide catheter, then the maximumdiameter of the electrode 46 is constrained to about 0.070 inches. Inthe event a 5 French guide catheter is used, then maximum diameter ofthe electrode 46 is constrained to about 0.053 inches. Based upon theseconstraints and the aforementioned power delivery considerations, theelectrode 46 desirably has an outer diameter of from about 0.049 toabout 0.051 inches.

While it may be possible to provide a catheter apparatus or devicehaving multiple electrodes at or proximate to the distal end of theapparatus, it is desirable for the catheter apparatus described hereinto have only a single electrode at or proximate to the distal end. Thereare several reasons why a single electrode apparatus may have clinicaland/or functional benefits over a multiple electrode apparatus. Forexample, as indicated below, an electrode with a relatively largesurface area may create larger, more effective lesions via increasedenergy delivery and higher power since blood flow carries away excessheat and effectively cools the electrode. As discussed above, themaximum diameter/crossing profile of the electrode is constrained by theinner diameter of the guide catheter through which the electrode isdelivered. It would be difficult for a multiple electrode apparatus tohave electrodes that are as large as a single electrode at the distalend of the apparatus since the crossing profile of the multipleelectrodes would have to take into account the diameter of the apparatusshaft. Attempts to design an apparatus having multiple electrodes thatindividually approach the surface area of a single electrode at thedistal end are expected to increase complexity and cost. Additionally,multiple electrode arrangements can also increase stiffness of theapparatus, which may not only compromise the deliverability of theapparatus, but also increase risk of injury to the blood vessels. Forexample, a catheter apparatus that is too stiff would not be able tomake the significant bend that is necessary to access a renal arteryfrom the abdominal aorta.

Not only may delivery to and through a tortuous blood vessel, such as arenal artery, be difficult with a multiple electrode apparatus, butplacement and use within a tortuous blood vessel may also bechallenging. Since vascular anatomy may vary significantly because oftortuosity and the unpredictable location of vessel branches and vesseldisease (e.g., atherosclerosis) successful delivery and placement of anapparatus can be very complicated with multiple electrodes.Additionally, it would be very difficult to ensure proper wall contactfor all electrodes due to the variable anatomy of the vessel wheretreatment is to be administered. Although sensors and software could bedeveloped and implemented to address some of these issues, it wouldincrease the cost of the system and increase complexity for the user.Hence, a single electrode apparatus such as that described herein may bemore effective than a multiple electrode apparatus, particularly intortuous blood vessels where there is a high degree of anatomicvariability.

D. Applying Energy to Tissue Via the Thermal Heating Element

Referring back to FIG. 5, in the illustrated embodiment, the generator26 may supply to the electrode 46 a pulsed or continuous RF electricfield. Although a continuous delivery of RF energy is desirable, theapplication of thermal energy in pulses may allow the application ofrelatively higher energy levels (e.g., higher power), longer or shortertotal duration times, and/or better controlled intravascular renalneuromodulation therapy. Pulsed energy may also allow for the use of asmaller electrode.

The thermal therapy may be monitored and controlled, for example, viadata collected with thermocouples, impedance sensors, pressure sensors,optical sensors or other sensors 52 (see FIG. 9A), which may beincorporated into or on electrode 46 or in/on adjacent areas on thedistal end region 20. Additionally or alternatively, variousmicrosensors can be used to acquire data corresponding to the thermalheating element, the vessel wall and/or the blood flowing across thethermal heating element. For example, arrays of micro thermocouplesand/or impedance sensors can be implemented to acquire data along thethermal heating element or other parts of the treatment device. Sensordata can be acquired or monitored prior to, simultaneous with, or afterthe delivery of energy or in between pulses of energy, when applicable.The monitored data may be used in a feedback loop to better controltherapy, e.g., to determine whether to continue or stop treatment, andit may facilitate controlled delivery of an increased or reduced poweror a longer or shorter duration therapy.

Non-target tissue may be protected by blood flow (F) within therespective renal artery as a conductive and/or convective heat sink thatcarries away excess thermal energy. For example (as FIGS. 9A and 9Bshow), since blood flow (F) is not blocked by the elongated shaft 16 andthe electrode 46 it carries, the native circulation of blood in therespective renal artery serves to remove excess thermal energy from thenon-target tissue and the thermal heating element. The removal of excessthermal energy by blood flow also allows for treatments of higher power,where more energy can be delivered to the target tissue as thermalenergy is carried away from the electrode and non-target tissue. In thisway, intravascularly-delivered thermal energy heats target neural fiberslocated proximate to the vessel wall to modulate the target neuralfibers, while blood flow (F) within the respective renal artery protectsnon-target tissue of the vessel wall from excessive or undesirablethermal injury. When energy is delivered in pulses, the time intervalbetween delivery of thermal energy pulses may facilitate additionalconvective or other cooling of the non-target tissue of the vessel wallcompared to applying an equivalent magnitude or duration of continuousthermal energy.

In addition, or as an alternative, to utilizing blood flow (F) as a heatsink, a thermal fluid may be injected, infused, or otherwise deliveredinto the vessel to remove excess thermal energy and protect thenon-target tissues. The thermal fluid may, for example, comprise asaline or other biocompatible fluid. The thermal fluid may, for example,be injected through the treatment device 12 via an infusion lumen and/orport (not shown) or through a guide catheter at a location upstream froman energy delivery element, or at other locations relative to the tissuefor which protection is sought. The use of a thermal fluid may allow forthe delivery of increased/higher power, smaller electrode size and/orreduced treatment time.

Although many of the embodiments described herein pertain to electricalsystems configured for the delivery of RF energy, it is contemplatedthat the desired treatment can be can be accomplished by other means,e.g., by coherent or incoherent light; heated or cooled fluid;microwave; ultrasound (including high intensity focused ultrasound);diode laser; a tissue heating fluid; or cryogenic fluid.

III. Representative Embodiments

A. First Representative Embodiment (Proximal, Intermediate, and DistalFlexure Zones with Distally Carried Thermal Heating Element 24)

FIGS. 10A to 15H show a representative embodiment of an elongated shaft16 that includes a proximal force transmitting section 30, as well asproximal, intermediate and distal flexure zones 32, 34, and 44, havingthe physical and mechanical features described above. In thisembodiment, the thermal heating element 24 is carried distally of thedistal flexure zone 44 (see, e.g., FIG. 11A).

1. Force Transmitting Section

In the illustrated embodiment, as shown in FIGS. 10A and 10B, theproximal force transmitting section 30 comprises a first elongated anddesirably tubular structure, which can take the form of, e.g., a firsttubular structure 54. The first tubular structure 54 is desirably a hypotube that is made of a metal material, e.g. of stainless steel, or ashape memory alloy, e.g., nickel titanium (a.k.a., nitinol or NiTi), topossess the requisite axial stiffness and torsional stiffness, asalready described, for the force transmitting section 30. As alreadydescribed, the force transmitting section 30 comprises the most stiffsection along the elongated shaft 16, to facilitate axially movement ofthe elongated shaft 16, as well as rotational manipulation of theelongated shaft 16 within the intravascular path 14. Alternatively, thefirst tubular structure 54 may comprise a hollow coil, hollow cable,solid cable (w/ embedded wires), braided shaft, etc.

The stiffness is a function of material selection as well as structuralfeatures such as interior diameter, outside diameter, wall thickness,geometry and other features that are made by micro-engineering,machining, cutting and/or skiving the hypo tube material to provide thedesired axial and torsional stiffness characteristics. For example, theelongated shaft can be a hypo tube that is laser cut to various shapesand cross-sectional geometries to achieve the desired functionalproperties.

When the first tubular structure 54 is made from an electricallyconductive metal material, the first tubular structure 54 includes asheath 56 or covering made from an electrically insulating polymermaterial or materials, which is placed over the outer diameter of theunderlying tubular structure. The polymer material can also be selectedto possess a desired durometer (expressing a degree of stiffness or lackthereof) to contribute to the desired overall stiffness of the firsttubular structure 54. Candidate materials for the polymer materialinclude polyethylene terephthalate (PET); Pebax® material; nylon;polyurethane, Grilamid® material or combinations thereof. The polymermaterial can be laminated, dip-coated, spray-coated, or otherwisedeposited/attached to the outer diameter of the tube.

2. Proximal Flexure Zone

As FIGS. 11A, 11B, and 11C show, the proximal flexure zone 32 comprisesa second elongated and desirably tubular structure, which can take theform of, e.g., a second tubular structure 58. The second tubularstructure 58 can be made from the same or different material as thefirst tubular structure 54. The axial stiffness and torsional stiffnessof the second tubular structure 58 possesses the requisite axialstiffness and torsional stiffness, as already described, for theproximal flexure zone 32. As already described, the proximal flexurezone 32 may be less stiff and more flexible than the force transmittingsection 30, to navigate the severe bend at and prior to the junction ofthe aorta and respective renal artery. The second tubular structure isdesirably a hypo tube, but can alternatively comprise a hollow coil,hollow cable, braided shaft, etc.

It may be desirable for the first and second tubular structures 54 and58 to share the same material. In this event, the form and physicalfeatures of the second tubular structure 58 may be altered, compared tothe first tubular structure 54, to achieve the desired stiffness andflexibility differences. For example, the interior diameter, outsidediameter, wall thickness, and other engineered features of the secondtubular structure 58 can be tailored to provide the desired axial andtorsional stiffness and flexibility characteristics. For example, thesecond tubular structure 58 can be laser cut along its length to providea bendable, spring-like structure. Depending on the ease ofmanufacturability the first and second tubular structures may beproduced from the same piece of material or from two separate pieces. Inthe event the first tubular structure and second tubular structure arenot of the same material, the outside diameter of the second tubularstructure 58 can be less than the outer diameter of first tubularstructure 54 (or have a smaller wall thickness) to create the desireddifferentiation in stiffness between the first and second tubularstructures 54 and 58.

When the second tubular structure 58 is made from an electricallyconductive metal material, the second tubular structure 58, like thefirst tubular structure 54, includes a sheath 60 (see FIGS. 11B and 11C)or covering made from an electrically insulating polymer material ormaterials, as already described. The sheath 60 or covering can also beselected to possess a desired durometer to contribute to the desireddifferentiation in stiffness and flexibility between the first andsecond tubular structures 58.

The second tubular structure 58 can comprise a different material thanthe first tubular structure 54 to impart the desired differentiation instiffness and flexibility between the first and second tubularstructures 58. For example, the second tubular structure 58 can comprisea cobalt-chromium-nickel alloy, instead of stainless steel.Alternatively, the second tubular structure 58 can comprise a less rigidpolymer, braid-reinforced shaft, nitinol or hollow cable-like structure.In addition to material selection, the desired differentiation instiffness and overall flexibility can be achieved by selection of theinterior diameter, outside diameter, wall thickness, and otherengineered features of the second tubular structure 58, as alreadydescribed. Further, a sheath 60 or covering made from an electricallyinsulating polymer material, as above described, can also be placed overthe outer diameter of the second tubular structure 58 to impart thedesired differentiation between the first and second tubular structures54 and 58.

3. Intermediate Flexure Zone

As FIGS. 12A, 12B, 12C, and 12D show, the intermediate flexure zone 34comprises a third elongated and desirably tubular structure, which cantake the form of, e.g., a third tubular structure 62. The third tubularstructure 62 can be made from the same or different material as thefirst and/or second tubular structures 54 and 58. The axial stiffnessand torsional stiffness of the third tubular structure 62 possesses therequisite axial stiffness and torsional stiffness, as already described,for the intermediate flexure zone 34. As already described, theintermediate flexure zone 34 may be less stiff and more flexible thanthe proximal flexure zone 32, to facilitate controlled deflection of theintermediate flexure zone 34 within the respective renal artery.

If the second and third tubular structures 58 and 62 share the samematerial, the form and physical features of the third tubular structure62 are altered, compared to the second tubular structure 58, to achievethe desired stiffness and flexibility differences. For example, theinterior diameter, outside diameter, wall thickness, and otherengineered features of the third tubular structure 62 can be tailored toprovide the desired axial and torsional stiffness and flexibilitycharacteristics. For example, the third tubular structure 62 can belaser cut along its length to provide a more bendable, more spring-likestructure than the second tubular structure 58.

When the third tubular structure 62 is made from an electricallyconductive metal material, the third tubular structure 62 also includesa sheath 64 (see FIGS. 12B, 12C, and 12D) or covering made from anelectrically insulating polymer material or materials, as alreadydescried. The sheath 64 or covering can also be selected to possess adesired durometer to contribute to the desired differentiation instiffness and flexibility between the second and third tubular structure62 s.

The third tubular structure 62 can comprise a different material thanthe second tubular structure to impart the desired differentiation instiffness and flexibility between the second and third tubularstructures 62. For example, the third tubular structure 62 can include aNitinol material, to impart the desired differentiation in stiffnessbetween the second and third tubular structures 58 and 62. In additionto material selection, the desired differentiation in stiffness andoverall flexibility can be achieved by selection of the interiordiameter, outside diameter, wall thickness, and other engineeredfeatures of the third tubular structure 62, as already described.

For example, in diameter, the outside diameter of the third tubularstructure 62 is desirably less than the outer diameter of second tubularstructure 58. Reduction of outside diameter or wall thickness influencesthe desired differentiation in stiffness between the second and thirdtubular structures 58 and 62.

As discussed in greater detail above, preferential deflection of theintermediate flexure zone is desirable. This can be achieved by makingthe third tubular structure 62 less stiff in the desired direction ofdeflection and/or more stiff opposite the direction of deflection. Forexample, as shown in FIGS. 12B and 12C, the third tubular structure 62(unlike the second tubular structure 58) can include a laser-cut patternthat includes a spine 66 with connecting ribs 68. The pattern biases thedeflection of the third tubular structure 62, in response to pulling onthe control wire 40 coupled to the distal end of the third tubularstructure 62, toward a desired direction. The control wire 40 isattached to a distal end of the intermediate flexure zone with solder130. The benefits of preferential deflection within a renal artery havealready been described.

As also shown in FIG. 12D, a flat ribbon material 70 (e.g., Nitinol,stainless steel, or spring stainless steel) can be attached to the thirdtubular structure 62. When the pulling force is removed from the controlwire 40, the flat ribbon, which serves to reinforce the deflectablethird tubular structure 62, will straighten out the deflectable thirdtubular structure 62.

Further, a sheath 72 (see FIGS. 12B, 12C, and 12D) or covering made froman electrically insulating polymer material, as above described, andhaving a desired durometer can also be placed over the outer diameter ofthe second tubular structure 58 to impart the desired differentiationbetween the first and second tubular structures 54 and 58.

Preferential deflection from reduced stiffness in the direction ofdeflection, as described above, can be achieved in a number ofadditional ways. For example, as FIGS. 13B and 13C show, the thirdtubular structure 62 can comprise a tubular polymer or metal/polymercomposite having segments with different stiffnesses D1 and D2, in whichD1>D2 (that is, the segment with D1 is mechanically stiffer than thesegment with D2. The third tubular structure 62 can also take the formof an oval, or rectangular, or flattened metal coil or polymer havingsegments with different stiffnesses D1 and D2, in which D1>D2 (as shownin FIG. 13C). In either arrangement, the segment having the lowerstiffness D2 is oriented on the third tubular structure 62 on the sameside as the actuator wire is attached.

Alternatively, as FIGS. 14B and 14C show, the third tubular structure 62can comprise an eccentric polymer or metal/polymer composite, which canbe braided or coiled. The third tubular structure 62 can also take theform of an eccentric oval, or rectangular, or flattened metal coil orpolymer (as FIG. 14C shows). In either arrangement, the thinner wallsegment 76 (less stiff) is oriented on the third tubular structure 62 onthe same side as the actuator wire attached.

4. Distal Flexure Zone

As shown in FIGS. 15A to 15H, the distal flexure zone 44 comprises aspring-like flexible tubular structure 74. The flexible structure 74 cancomprise a metal, a polymer, or a metal/polymer composite. The materialand physical features of the flexible structure 74 are selected so thatthe axial stiffness and torsional stiffness of the flexible structure 74is not greater than the axial stiffness and torsional stiffness of thethird tubular structure 62. The overall flexibility of the flexiblestructure 74 is at least equal to and desirably greater than theflexibility of third tubular structure 62 when the third tubularstructure has not been deflected by the control wire 40.

As shown in FIG. 15B, the thermal heating element 24 is carried at thedistal end of the flexible structure 74 for placement in contact withtissue along a vessel wall of a respective renal artery.

The material selected for the flexible structure 74 can be radiopaque ornon-radiopaque. Desirably, the flexible member includes a radiopaquematerial, e.g., stainless steel, platinum, platinum iridium, or gold, toenable visualization and image guidance. Alternatively, a non-radiopaquematerial can be used that is doped with a radiopaque substance, such asbarium sulfate.

The configuration of the flexible structure 74 can vary. For example, inthe embodiment depicted in FIGS. 15B and 15C, the flexible structure 74comprises a thread 104 encased in or covered with a polymer coating orwrapping 110. The thread 104 is routed through a proximal anchor 108,which is attached to the distal end of the intermediate flexure zone 34,and a distal anchor 106, which is fixed within or integrated into theheating element 24/electrode 46 using solder. Although various types ofmaterials can be used to construct the aforementioned structures, inorder to have a flexible structure 74 that securely connects to theintermediate flexure zone 34 and the thermal heating element 24, it isdesirable for thread 104 to be comprised of Kevlar or similar polymerthread and for the proximal anchor 108 and distal anchor 106 to becomprised of stainless steel. While the coating 110 can be comprised ofany electrically insulative material, and particularly those listedlater with respect to sheath 80, is desirable for the structures of theflexible structure 74 to be encased/coated/covered by a low-durometerpolymer such as carbothane laminate 110. As shown in FIG. 15C, one ormore supply wires 112 may run alongside or within the flexible structure74. As previously mentioned these wires may provide the thermal heatingelement 24 with electrical current/energy from the generator 26 and alsoconvey data signals acquired by sensor 52. Also as previously mentionedand depicted in FIG. 15C, the control wire 40 from the handle actuator42 can be formed into the proximal anchor 108 and attached to theelongated shaft using solder 130.

One advantage of the above-described configuration of the flexiblestructure 74 is that the flexible structure 74 creates a region ofelectrical isolation between the thermal heating element and the rest ofthe elongated shaft. Both the Kevlar thread 104 and laminate 110 areelectrically insulative, thereby providing the supply wire(s) 112 as thesole means for electrical connectivity.

As shown in FIGS. 15D through 15F, the flexible structure 74 allowsconsiderable passive deflection of the distal flexure zone 44 when thethermal heating element 24 is put into contact with the vessel wall. Asalready described, this flexibility has several potential benefits. Thesize and configuration of the flexible structure 74 enables the thermalheating element to deflect in many directions because the distal flexurezone may bend by angle Θ in any plane through the axis of the distal endregion. For treatments within a peripheral blood vessel such as therenal artery, it is desirable that angle Θ≦90 degrees.

In alternative embodiments for the distal flexure zone 44, the flexiblestructure 74 can take the form of a tubular metal coil, cable, braid orpolymer, as FIG. 15H shows. Alternatively, the flexible structure 74 cantake the form of an oval, or rectangular, or flattened metal coil orpolymer, as FIG. 15G shows. In alternate embodiments, the flexiblestructure 74 may comprise other mechanical structures or systems thatallow the thermal heating element 24 to pivot in at least one plane ofmovement. For example, the flexible structure 74 may comprise a hinge orball/socket combination.

The flexible structure 74 as a part of the distal flexure zone can becoupled to the intermediate flexure zone as describe above.Alternatively, in embodiments that do not provide an intermediateflexure zone, the distal flexure zone can be coupled to the proximalflexure zone. Still alternatively, the distal flexure zone can becoupled to an intermediate section comprising an arch wire as describedin co-pending patent application Ser. No. 12/159,306, filed Jun. 26,2008, which is incorporated herein in its entirety. For example, FIGS.15I and 15J provide a catheter comprising a shaft 16 and a distal endregion 20, wherein the distal end region 20 comprises an intermediatesection 34, a distal flexure zone 44 and a thermal heating element 24.More specifically, the catheter may comprise an intermediate sectioncomprising an arch wire 114, a distal flexure zone comprising a flexiblestructure, and a thermal heating element comprising an electrode 46,wherein the flexible structure is coupled to the arch wire andelectrode.

If the flexible member comprises, in whole or in part, an electricallyconductive material, the distal flexure zone 44 desirably includes anouter sheath 80 (see FIGS. 15G and 15H) or covering over the flexiblestructure 74 made from an electrically insulating polymer material. Thepolymer material also possesses a desired durometer for flexibility ofthe flexible member (e.g., 25D to 55D).

Candidate materials for the polymer material include polyethyleneterephthalate (PET); Pebax; polyurethane; urethane, carbothane,tecothane, low density polyethylene (LDPE); silicone; or combinationsthereof. The polymer material can be laminated, dip-coated,spray-coated, or otherwise deposited/applied over the flexible structure74. Alternatively, a thin film of the polymer material (e.g., PTFE) canbe wrapped about the flexible structure 74. Alternatively, the flexiblestructure 74 can be inherently insulated, and not require a separatesheath 56 or covering. For example, the flexible member can comprise apolymer-coated coiled wire.

5. Rotation Controller

As will be discussed later in greater detail, it is desirable to rotatethe device within the renal artery after the thermal heating element isin contact the vessel wall. However, it may be cumbersome and awkwardfor a clinical practitioner to rotate the entire handle at the proximalend of the device, particularly given the dimensions of the renalanatomy. In one representative embodiment, as shown in FIGS. 16A and16B, the proximal end of the shaft 16 is coupled to the handle 22 by arotating fitting 82.

The rotating fitting 82 is mounted by a tab 84 (see FIG. 16B) carried ina circumferential channel 86 formed on the distal end of the handle 22.The rotating fitting 82 can thus be rotated at the distal end of thehandle 22 independent of rotation of the handle 22.

The proximal end of the force transmitting section 30 is attached to astationary coupling 88 on the rotating fitting 82. Rotation of therotating fitting 82 (as FIG. 16A shows) thereby rotates the forcetransmitting section 30, and, with it, the entire elongated shaft 16,without rotation of the handle 22. As FIG. 16A shows, a caregiver isthereby able to hold the proximal portion of the handle 22 rotationallystationary in one hand and, with the same or different hand, apply atorsional force to the rotating fitting 82 to rotate the elongated shaft16. This allows the actuator to remain easily accessed for controlleddeflection.

Since there are cables and wires running from the handle through theshaft of the device (e.g., actuation wire/cable, electrical transmissionwire(s), thermocouple wire(s), etc.), it is desirable to limit rotationof the shaft relative to these wires in order to avoid unnecessaryentanglement and twisting of these wires. The handle embodiment depictedin FIG. 16C provides a rotational limiting element to address this need.In this embodiment, the rotating fitting 82 includes an axial groove 116and the distal portion of the handle 22 comprises a fitting interface118 having a helical channel 120. A ball 122 comprising stainless steelor another metal or a polymer is placed within the fitting interface 118so that it, upon rotation of the fitting, may simultaneously travelwithin the helical channel 120 of the fitting interface 118 and alongthe axial groove 116 of the fitting. When the ball 122 reaches the endof the channel and/or groove, the ball will no longer move and,consequently, the fitting will not be able to rotate any further in thatdirection. The rotational fitting 82 and handle fitting interface 118can be configured to allow for the optimal number of revolutions for theshaft, given structural or dimensional constraints (e.g., wires). Forexample, the components of the handle could be configured to allow fortwo revolutions of the shaft independent of the handle.

As has been described and will be described in greater detail later, byintravascular access, the caregiver can manipulate the handle 22 tolocate the distal end region 20 of the elongated shaft 16 within therespective renal artery. The caregiver can then operate the actuator 42on the handle 22 (see FIG. 16A) to deflect the thermal heating element24 about the intermediate flexure zone 34. The caregiver can thenoperate the rotating fitting 82 on the handle 22 (see FIGS. 16A and 16D)to apply a rotational force along the elongated shaft 16. The rotationof the elongated shaft 16 when the intermediate flexure zone 34 isdeflected within the respective renal artery rotates the thermal heatingelement 24 within the respective renal artery, making it easier toachieve contact with the vessel wall and determine whether there is wallcontact, particularly in planes where there is poor angiographicvisualization.

In an additional aspect of the disclosed technology, the handle 22 maybe configured to minimize operator/caregiver handling of the devicewhile it is within the patient. As shown in FIG. 16D, the handle alsocomprises a lower surface 132 that substantially conforms to the surfacebeneath (e.g., operating table). This lower surface 132, which is shownto be substantially flat in FIG. 16D, can alternatively be curved,shaped or angled depending on the configuration and/or geometry of thebeneath surface. The conforming lower surface 132 enables the clinicaloperator to keep the handle 22 stable when the treatment device 12 iswithin the patient. In order to rotate the device when it is inside thepatient, the operator can simply dial the rotating fitting 82 withoutany need to lift the handle. When the operator desires to retract thedevice for subsequent treatments, the operator can simply slide thehandle along the beneath surface to the next position. Again, thismitigates the risk of injury due to operator error or over handling ofthe treatment device. Additionally or alternatively, the lower surfacecan engage the surface underneath using clips, texture, adhesive, etc.

Additional enhancements to the rotation mechanism disclosed hereininclude providing tactile and/or visual feedback on the rotationalfitting so that the operator can exercise greater control and care inrotating the device. The rotating fitting 82 can also be selectivelylocked to the interface, thereby preventing further rotation, if theoperator wishes to hold the treatment device in a particular angularposition. Another potential enhancement includes providing distancemarkers along the shaft/handle to enable the operator to gage distancewhen retracting the treatment device.

B. Second Representative Embodiment (Distal Flexure Zone Comprises aFlexible Active Electrode)

FIGS. 17A and 17B show a representative embodiment of an elongated shaft16 that includes a proximal force transmitting section 30, proximalflexure zone 32, intermediate flexure zone 34, and a distal flexure zone44. In this embodiment, the materials, size, and configuration of theproximal force transmitting section 30, proximal flexure zone 32, andintermediate flexure zone 34 are comparable to the respectivecounterparts described in the first representative embodiment.

In this embodiment, however, the distal flexure zone 44 is sized andconfigured to itself serve as an active, flexible electrode 90. Indiameter, the active, flexible electrode 90 is sized and configured tobe equal to or greater than the intermediate flexure zone 34. The totalsurface area TSA of the active, flexible electrode 90 is therebyincreased, so that the possible active surface area of the electrode 46is increased as well.

Also, in this arrangement, the entire length of the active flexibleelectrode 90 shares the flexibility properties of the distal flexurezone 44, as previously described. Materials are selected that, inaddition to imparting the desired flexibility, are electricallyconductive as well. The active electrode 90 is thereby flexible enoughalong its entire length to conform closely against the vessel wall,thereby further increasing the possible active surface area of theelectrode. The active flexible electrode 90 may also more readilydeflect away from the vessel wall when engaging the vessel wall head-on,to thereby minimize the forces exerted against the vessel wall as theelectrode 90 is placed into side-on relationship with the vessel wall.The active, flexible electrode 90 can thereby be considered moreatraumatic.

In the illustrated embodiment, the active, flexible electrode 90 furtherdesirably includes a distal region that is tapered to form a blunt,atraumatic end surface 48. The end surface 48 can be formed from metalmaterials by laser, resistive welding, or machining techniques. The endsurface 48 can also be formed from polymer materials by bonding,lamination, or insert molding techniques.

C. Third Representative Embodiment (Distal Flexure Zone IncludesSubstantially Spherical Active Electrode)

FIGS. 18A and 18B show a representative embodiment of an elongated shaft16 that includes a proximal force transmitting section 30, proximalflexure zone 32, and a intermediate flexure zone 34, and a distalflexure zone 44. In this embodiment, the materials, size, andconfiguration of the proximal force transmitting section 30, proximalflexure zone 32, and intermediate flexure zone 34 are comparable to therespective counterparts in the first and second embodiments.

In this embodiment, however, the distal flexure zone 44 is sized andconfigured to carry a substantially spherical or cylindrical activeelectrode 92 at a location more proximally spaced from its distal end.In this embodiment, the distal flexure zone 44 shares the flexibilitycharacteristics of the distal flexure zone 44, as previously described.In diameter, however, the distal flexure zone 44 is sized and configuredto be approximately equal to the intermediate flexure zone 34. Indiameter, the spherical active electrode 92 is sized to be larger thanthe diameter of the distal flexure zone 44. Therefore, flexure of thedistal flexure zone 44 can place the spherical electrode 92 into contactwith a greater tissue area, thereby increasing the active surface area(ASA) of the electrode.

In the illustrated embodiment, the distal flexure zone 44 desirablyincludes a distal region that is tapered to form a blunt, atraumatic endsurface 48. The end surface 48 can be formed from metal materials bylaser, resistive welding, or machining techniques. The end surface 48can also be formed from polymer materials by bonding, lamination, orinsert molding techniques.

The spherical electrode 92 can be attached to the distal flexure zone 44e.g., by spot welding, laser welding, or soldering techniques. Theplacement of the spherical electrode 92 along the length of the distalflexure zone 44 can vary. It can be placed, e.g., in the approximatemid-region of the distal flexure zone 44, or closer to the distal endthan the proximal end, or vice versa.

IV. Use of the System

A. Intravascular Delivery, Deflection and Placement of the TreatmentDevice

Any one of the embodiments of the treatment devices 12 described hereincan be delivered over a guide wire using conventional over-the-wiretechniques. When delivered in this manner (not shown), the elongatedshaft 16 includes a passage or lumen accommodating passage of a guidewire.

Alternatively, any one of the treatment devices 12 described herein canbe deployed using a conventional guide catheter or pre-curved renalguide catheter 94.

When using a guide catheter 94 (see FIG. 6A), the femoral artery isexposed and cannulated at the base of the femoral triangle, usingconventional techniques. In one exemplary approach, a guide wire (notshown) is inserted through the access site and passed using imageguidance through the femoral artery, into the iliac artery and aorta,and into either the left or right renal artery. A guide catheter can bepassed over the guide wire into the accessed renal artery. The guidewire is then removed. Alternatively, a renal guide catheter (shown inFIG. 19A), which is specifically shaped and configured to access a renalartery, can be used to avoid using a guide wire. Still alternatively,the treatment device can be routed from the femoral artery to the renalartery using angiographic guidance and without the need of a guidecatheter.

When a guide catheter is used, at least three delivery approaches can beimplemented. In one exemplary approach, one or more of theaforementioned delivery techniques can be used to position a guidecatheter within the renal artery just distal to the entrance of therenal artery. The treatment device is then routed via the guide catheterinto the renal artery. Once the treatment device is properly positionedwithin the renal artery, the guide catheter is retracted from the renalartery into the abdominal aorta. In this approach, the guide cathetershould be sized and configured to accommodate passage of the treatmentdevice. For example, a 6 French guide catheter can be used.

In a second exemplary approach, a first guide catheter is placed at theentrance of the renal artery (with or without a guide wire). A secondguide catheter is passed via the first guide catheter (with or withoutthe assistance of a guide wire) into the renal artery. The treatmentdevice is then routed via the second guide catheter into the renalartery. Once the treatment device is properly positioned within therenal artery the second guide catheter is retracted, leaving the firstguide catheter at the entrance to the renal artery. In this approach thefirst and second guide catheters should be sized and configured toaccommodate passage of the second guide catheter within the first guidecatheter (i.e., the inner diameter of the first guide catheter should begreater than the outer diameter of the second guide catheter). Forexample, the first guide catheter could be 8 French in size and thesecond guide catheter could be 5 French in size.

In a third exemplary approach, and as shown in FIG. 19A, a renal guidecatheter 94 is positioned within the abdominal aorta, just proximal tothe entrance of the renal artery. As now shown in FIG. 19B, thetreatment device 12 as described herein is passed through the guidecatheter 94 and into the accessed renal artery. The elongated shaftmakes atraumatic passage through the guide catheter 94, in response toforces applied to the force transmitting section 30 through the handle22. The proximal flexure zone 32 accommodates significant flexure at thejunction of the left/right renal arteries and aorta to gain entry intothe respective left or right renal artery through the guide catheter 94(as FIG. 19B shows).

As FIG. 19C shows, the intermediate flexure zone 34 on the distal endportion of the elongated shaft 16 can now be axially translated into therespective renal artery, remotely deflected and/or rotated in acontrolled fashion within the respective renal artery to attainproximity to and a desired alignment with an interior wall of therespective renal artery. As FIG. 19C further shows, the distal flexurezone 44 bends to place the thermal energy heating element into contactwith tissue on the interior wall.

As FIG. 19D shows, the complex, multi-bend structure formed by theproximal, intermediate and distal zones 32, 24, and 44 of the distal endregion 20 of the elongated shaft 16 creates a consistent and reliableactive surface area of contact between the thermal heating element 24and tissue within the respective renal artery (refer back to FIG. 8C).Thermal energy can now be applied through the thermal heating element 24to induce one or more thermal heating effects on localized regions oftissue along the respective renal artery.

B. Facilitating Contact with the Vessel Wall

As previously described, the actuation of the control wire 40 to deflectthe intermediate flexure zone 32 helps position the thermal heatingelement 24 in contact with the vessel wall. This is particularly usefulwhen the distal end region 20 of the treatment device 12 is deliveredinto the renal artery, as shown in FIG. 19B. Due to the curve andplacement of the renal guide catheter 94 and orientation of thetreatment device 12, the distal end region 20 of the treatment device isoriented up against the superior region of the vessel wall when firstdelivered into the renal artery, as shown in FIG. 19B. Once the distalend region is positioned at the most distal portion of the main renalartery, the operator may deflect the intermediate flexure zone 34 viathe actuator 42 to position the thermal heating element 24 into contactwith the vessel wall at a more inferior location, as shown in FIG. 19C.This deflection of the intermediate flexure zone 34 establishes wallcontact and provides, via the distal flexure zone 44, a stabilizingforce between the thermal heating element 24 and vessel wall to positionthe thermal heating element in contact with the vessel wall. Theoperator can then initiate treatment at this generally inferior (bottom)location or rotate the treatment device as shown in FIG. 19E for analternate treatment location.

The active deflection of intermediate flexure zone 34 is facilitated bynot only operation of actuator 42, but also contact between a proximalregion of the intermediate flexure zone 44 and a superior region of therenal artery. As shown in FIG. 19C, this contact region 124 generallyoccurs at the apex of the bend of the intermediate flexure zone 34. Thiscontact region 124 is in radial opposition to the contact between thethermal heating element 24 and vessel wall following deflection of theintermediate flexure zone 34. The stabilizing force provided by theintermediate flexure zone 44 to the thermal heating element 24 is alsofacilitated by the opposing force at contact region 124. Even when theoperator rotates the treatment device to circumferentially repositionthe thermal heating element, as shown in FIG. 19E, this oppositioncontact will be maintained, but at a different circumferential position.FIG. 19F shows the circumferential rotation of the thermal heatingelement 24 from a first treatment location corresponding to lesion 98(a)to a second treatment location corresponding to lesion 98(b) and thecircumferential translation of the intermediate flexure zone 32 to a newcontact region 124. It should be noted, however, that while having suchopposition contact at contact region 124 facilitates wall contact andthe stabilizing force, it is not generally required to achieve contactbetween the thermal heating element 24 and the vessel wall.

It certain embodiments, it may also be beneficial to equip the catheterapparatus with a second thermal heating element (not shown) at or in thevicinity of the intermediate flexure zone. Placement of the secondthermal heating element on or proximate to the intermediate flexure zonemay enable the creation of a thermally affected tissue region at oraround contact region 124 (i.e., the portion of the vessel wall that isin contact with the intermediate flexure zone). Activation of the firstthermal element and the second thermal element would allow the operatorto create two treatment zones that are circumferentially andlongitudinally offset during a single placement of the catheterapparatus.

As described above, the size and configuration of the intermediateflexure zone 34 play a valuable role in the positioning of the devicefor treatment and in facilitating contact between the thermal heatingelement and the vessel wall. The dimensioning of the intermediateflexure zone also plays a valuable role in this regard, particularlywith respect to the constraints imposed by the renal anatomy.

Referring back to FIG. 7E, the length of the main branch of a renalartery (i.e., from the junction of the aorta and renal artery to justbefore the artery branches into multiple blood vessels going to thekidney) is RA_(L) and the diameter of the main branch of a renal arteryis RA_(DIA). It is desirable for the length L3 of the intermediateflexure zone 34 to be long enough for the distal end region 20 of thetreatment device 12 to reach a distal treatment location within therenal artery and, to be able to, upon deflection, translate the thermalheating element 24 to the radially opposite wall of the renal artery.However, if L3 were too long, then too much of the intermediate flexurezone's proximal region would reside within the aorta (even for distaltreatments), thereby preventing contact at contact region 124 since theapex of the bend of the intermediate flexure zone would likely be in theaorta. Also, an L3 that is too long would deflect with a large radius ofcurvature (i.e., a2) and make it difficult for the operator to reliablyachieve wall contact at both distal and proximal locations.

Additionally, as a practical matter, L3 is limited by the most distaltreatment location (i.e., length of the renal artery) on one end and thelocation within the aorta of the renal guide catheter 94 on the otherend. It would be undesirable for L3 to be so long that a portion of theintermediate flexure zone resides within the renal guide catheter duringdistal treatments since the deflection of the intermediate flexure zonewithin the guide could impair the ability of the operator to rotate andtorque the catheter without whipping.

In an average human renal artery, RA_(L) is about 20 mm to about 30 mmfrom the junction of the aorta and renal artery and the diameter of themain branch of a renal artery RA_(DIA) is typically about 3 mm to about7 mm or 8 mm. Given these and the above considerations, it is desirablethat L3 range from about 5 mm to about 15 mm. In certain embodiments,particularly for treatments in relatively long blood vessels, L3 can beas long as about 20 mm. In another representative embodiment, L3 can beabout 12.5 mm.

C. Creation of Thermally Affected Tissue Regions

As previously described (and as FIG. 19B shows), the thermal heatingelement 24 can be positioned by bending along the proximal flexure zone32 at a first desired axial location within the respective renal artery.As FIG. 19C shows, the thermal heating element 24 can be radiallypositioned by deflection of intermediate flexure zone 34 toward thevessel wall. As FIG. 19C also shows, the thermal heating element 24 canbe placed into a condition of optimal surface area contact with thevessel wall by further deflection of the distal flexure zone 44.

Once the thermal heating element 24 is positioned in the desiredlocation by a combination of deflection of the intermediate flexure zone34, deflection of the distal flexure zone 44 and rotation of thecatheter, the first focal treatment can be administered. By applyingenergy through the thermal heating element 24, a first thermallyaffected tissue region 98(a) can be formed, as FIG. 19D shows. In theillustrated embodiment, the thermally affected region 98(a) takes theform of a lesion on the vessel wall of the respective renal artery.

After forming the first thermally affected tissue region 98(a), thecatheter needs to be repositioned for another thermal treatment. Asdescribed above in greater detail, it is desirable to create multiplefocal lesions that are circumferentially spaced along the longitudinalaxis of the renal artery. To achieve this result, the catheter isretracted and, optionally, rotated to position the thermal heatingelement proximally along the longitudinal axis of the blood vessel.Rotation of the elongated shaft 16 from outside the access site (seeFIG. 19E) serves to circumferentially reposition the thermal heatingelement 24 about the renal artery. Once the thermal heating element 24is positioned at a second axial and circumferential location within therenal artery spaced from the first-described axial position, as shown inFIG. 19E (e.g., 98(b)), another focal treatment can be administered. Byrepeating the manipulative steps just described (as shown in FIGS. 19Fthrough 19K), the caregiver can create several thermally affected tissueregions 98(a), 98(b), 98(c) and 98(d) on the vessel wall that areaxially and circumferentially spaced apart, with the first thermallyaffected tissue region 98(a) being the most distal and the subsequentthermally affected tissue regions being more proximal. FIG. 19I providesa cross-sectional view of the lesions formed in several layers of thetreated renal artery. This figure shows that several circumferentiallyand axially spaced-apart treatments (e.g., 98(a)-98(d)) can providesubstantial circumferential coverage and, accordingly, cause aneuromodulatory affect to the renal plexus. Clinical investigationindicates that each lesion will cover approximately 20-30 percent of thecircumferential area surrounding the renal artery. In other embodiments,the circumferential coverage of each lesion can be as much as 50percent.

In an alternative treatment approach, the treatment device can beadministered to create a complex pattern/array of thermally affectedtissue regions along the vessel wall of the renal artery. As FIG. 19Lshows, this alternative treatment approach provides for multiplecircumferential treatments at each axial site (e.g., 98, 99 and 101)along the renal artery. Increasing the density of thermally affectedtissue regions along the vessel wall of the renal artery using thisapproach might increase the probability of thermally-blocking the neuralfibers within the renal plexus.

The rotation of the thermal heating element 24 within the renal arteryas shown in FIG. 19G helps improve the reliability and consistency ofthe treatment. Since angiographic guidance such as fluoroscopy onlyprovides visualization in two dimensions, it is generally only possiblein the anterior/posterior view to obtain visual confirmation of wallcontact at the superior (vertex) and inferior (bottom) of the renalartery. For anterior and posterior treatments, it is desirable to firstobtain confirmation of contact at a superior or inferior location andthen rotate the catheter such that the thermal heating element travelscircumferentially along the vessel wall until the desired treatmentlocation is reached. Physiologic data such as impedance can beconcurrently monitored to ensure that wall contact is maintained oroptimized during catheter rotation. Alternatively, the C-arm of thefluoroscope can be rotated to achieve a better angle for determiningwall contact.

FIGS. 22A to 22C provide fluoroscopic images of the treatment devicewithin a renal artery during an animal study. FIG. 22A shows positioningof the treatment device and thermal heating element 24 at a distaltreatment location. The intermediate flexure zone 34 has been deflectedto position the thermal heating element 24 in contact with the vesselwall and to cause flexure in the distal flexure zone 44. FIG. 22A alsoshows contact region 124 where the apex of the bend of the intermediateflexure zone 34 is in contact with the vessel wall in radial oppositionto contact between the thermal heating element and vessel wall. FIG. 22Bshows the placement of the treatment device at a more proximal treatmentlocation following circumferential rotation and axial retraction. FIG.22C shows the placement of the treatment device at a proximal treatmentlocation just distal to the junction of the aorta and renal artery.

Since both the thermal heating element 24 and solder 130 at the distalend of the intermediate flexure zone 34 can be radiopaque, as shown inFIGS. 22A to 22C, the operator using angiographic visualization can usethe image corresponding to the first treatment location to relativelyposition the treatment device for the second treatment. For example, inrenal arteries of average length, it is desirable for the clinicaloperator to treat at about every 5 mm along the length of the mainartery. In embodiments where the length of the distal flexure zone 44 is5 mm, the operator can simply retract the device such that the currentposition of the thermal heating element 24 is longitudinally alignedwith the position of the solder 130 in the previous treatment.

In another embodiment, solder 130 can be replaced by a different type ofradiopaque marker. For example, a band of platinum can be attached tothe distal end of the intermediate flexure zone to serve as a radiopaquemarker.

Since angiographic visualization of the vasculature generally requirescontrast agent to be infused into the renal artery, it may be desirableto incorporate within or alongside the treatment device a lumen and/orport for infusing contrast agent into the blood stream. Alternatively,the contrast agent can be delivered into the blood alongside thetreatment device within the annular space between the treatment deviceand the guide catheter through which the device is delivered.

Exposure to thermal energy (heat) in excess of a body temperature ofabout 37° C., but below a temperature of about 45° C., may inducethermal alteration via moderate heating of the target neural fibers orof vascular structures that perfuse the target fibers. In cases wherevascular structures are affected, the target neural fibers are deniedperfusion resulting in necrosis of the neural tissue. For example, thismay induce non-ablative thermal alteration in the fibers or structures.Exposure to heat above a temperature of about 45° C., or above about 60°C., may induce thermal alteration via substantial heating of the fibersor structures. For example, such higher temperatures may thermallyablate the target neural fibers or the vascular structures. In somepatients, it may be desirable to achieve temperatures that thermallyablate the target neural fibers or the vascular structures, but that areless than about 90° C., or less than about 85° C., or less than about80° C., and/or less than about 75° C. Regardless of the type of heatexposure utilized to induce the thermal neuromodulation, a reduction inrenal sympathetic nerve activity (“RSNA”) is expected.

D. Control of Applied Energy

Desirably, the generator 26 includes programmed instructions comprisingan algorithm 102 (see FIG. 5) for controlling the delivery of energy tothe thermal heating device. The algorithm 102, as shown in FIG. 20, canbe implemented as a conventional computer program for execution by aprocessor coupled to the generator 26. Algorithm 102 is substantiallysimilar to the power delivery algorithm described in co-pending patentapplication Ser. No. 12/147,154, filed Jun. 26, 2008, which isincorporated herein by reference in its entirety. The algorithm 102 canalso be implemented manually by a caregiver using step-by-stepinstructions.

When a caregiver initiates treatment (e.g., via the foot pedal), thealgorithm 102 commands the generator 26 to gradually adjust its poweroutput to a first power level P₁ (e.g., 5 watts) over a first timeperiod t₁ (e.g., 15 seconds). The power increase during the first timeperiod is generally linear. As a result, the generator 26 increases itspower output at a generally constant rate of P₁/t₁. Alternatively, thepower increase can be non-linear (e.g., exponential or parabolic) with avariable rate of increase. Once P₁ and t₁ are achieved, the algorithmcan hold at P₁ until a new time t₂ for a predetermined period of timet₂−t₁ (e.g., 3 seconds). At t₂ power is increased by a predeterminedincrement (e.g., 1 watt) to P₂ over a predetermined period of time,t₃−t₂ (e.g., 1 second). This gradual power ramp can continue until amaximum power P_(MAX) is achieved or some other condition is satisfied.In one embodiment, P_(MAX) is 8 watts. In another embodiment P_(MAX) is10 watts.

The algorithm 102 includes monitoring certain operating parameters(e.g., temperature, time, impedance, power, etc.). The operatingparameters can be monitored continuously or periodically. The algorithm102 checks the monitored parameters against predetermined parameterprofiles to determine whether the parameters individually or incombination fall within the ranges set by the predetermined parameterprofiles. If the monitored parameters fall within the ranges set by thepredetermined parameter profiles, then treatment can continues at thecommanded power output. If monitored parameters fall outside the rangesset by the predetermined parameter profiles, the algorithm 102 adjuststhe commanded power output accordingly, For example, if a targettemperature (e.g., 65 degrees C.) is achieved, then power delivery iskept constant until the total treatment time (e.g., 120 seconds) hasexpired. If a first power threshold (e.g., 70 degrees C.) is achieved orexceeded, then power is reduced in predetermined increments (e.g., 0.5watts, 1.0 watts, etc.) until a target temperature is achieved. If asecond power threshold (e.g., 85 degrees C.) is achieved or exceeded,thereby indicating an undesirable condition, then power delivery can beterminated. The system can be equipped with various audible and visualalarms to alert the operator of certain conditions.

V. Prepackaged Kit for Distribution, Transport and Sale of the DisclosedApparatuses and Systems

As shown in FIG. 21, one or more components of the system 10 shown inFIG. 5 can be packaged together for convenient delivery to and use bythe customer/clinical operator. Components suitable for packaginginclude, the treatment device 12, the cable 28 for connecting thetreatment device 12 to the generator 26, the neutral or dispersiveelectrode 38, and one or more guide catheters 94 (e.g., a renal guidecatheter). Cable 28 can also be integrated into the treatment device 12such that both components are packaged together. Each component may haveits own sterile packaging (for components requiring sterilization) orthe components may have dedicated sterilized compartments within the kitpackaging. This kit may also include step-by-step instructions for use126 that provides the operator technical product features and operatinginstructions for using the system 10 and treatment device 12, includingall methods of insertion, delivery, placement and use of the treatmentdevice disclosed herein.

VI. Additional Clinical Uses of the Disclosed Apparatuses, Methods andSystems

Although much of the disclosure in this Specification relates to atleast partially denervating a kidney of a patient to block afferentand/or efferent neural communication from within a renal blood vessel(e.g., renal artery), the apparatuses, methods and systems describedherein may also be used for other intravascular treatments. For example,the aforementioned catheter system, or select aspects of such system,can be placed in other peripheral blood vessels to deliver energy and/orelectric fields to achieve a neuromodulatory affect by altering nervesproximate to these other peripheral blood vessels. There are a number ofarterial vessels arising from the aorta which travel alongside a richcollection of nerves to target organs. Utilizing the arteries to accessand modulate these nerves may have clear therapeutic potential in anumber of disease states. Some examples include the nerves encirclingthe celiac trunk, superior mesenteric artery, and inferior mesentericartery.

Sympathetic nerves proximate to or encircling the arterial blood vesselknown as the celiac trunk may pass through the celiac ganglion andfollow branches of the celiac trunk to innervate the stomach, smallintestine, abdominal blood vessels, liver, bile ducts, gallbladder,pancreas, adrenal glands, and kidneys. Modulating these nerves either inwhole (or in part via selective modulation) may enable treatment ofconditions including (but not limited to) diabetes, pancreatitis,obesity, hypertension, obesity related hypertension, hepatitis,hepatorenal syndrome, gastric ulcers, gastric motility disorders,irritable bowel syndrome, and autoimmune disorders such as Chron'sdisease.

Sympathetic nerves proximate to or encircling the arterial blood vesselknown as the inferior mesenteric artery may pass through the inferiormesenteric ganglion and follow branches of the inferior mesentericartery to innervate the colon, rectum, bladder, sex organs, and externalgenitalia. Modulating these nerves either in whole (or in part viaselective modulation) may enable treatment of conditions including (butnot limited to) GI motility disorders, colitis, urinary retention,hyperactive bladder, incontinence, infertility, polycystic ovariansyndrome, premature ejaculation, erectile dysfunction, dyspareunia, andvaginismus.

While arterial access and treatments have received attention in thisSpecification, the disclosed apparatuses, methods and systems can alsobe used to deliver treatment from within a peripheral vein or lymphaticvessel.

VII. Additional Description

The term apparatus makes reference to any apparatus of the disclosure.In particular, this term relates to devices for achieving intravascularrenal neuromodulation via thermal effects, such as heating. This termcovers references to apparatus catheters, catheters, and treatmentdevices in general. In the specific description, the term catheter isused, but it should be understood that this is merely a particularexample of the apparatuses of the disclosure.

Generally, the apparatus comprises an elongated shaft. The elongatedshaft is sized and configured to deliver a thermal element to a renalartery via an intravascular path that includes a femoral artery, aniliac artery, and the abdominal aorta. As described in more detailabove, different sectors of the elongated shaft serve differentmechanical functions when in use. The elongated shaft may be in the formof a flexible tube.

The term apparatus includes, but is not necessarily limited to, acatheter. As will be appreciated by one skilled in the art, a catheteris a solid or tubular structure that can be inserted into a body cavity,lumen, duct or vessel. A process of inserting a catheter iscatheterisation. The catheter, for example, may be an intravascularcatheter suitable for insertion into and delivery through anintravascular path.

The intravascular path may be via a femoral artery, an iliac artery,and/or the aorta. The passage may be through an access site,percutaneously into the femoral artery and passed into the iliac arteryand aorta, into either the left or right renal artery. This comprises anintravascular path that offers minimally invasive access to a respectiverenal artery and/or other renal blood vessels. For example, passagethrough an intravascular path comprises a first vascular region and asecond vascular region deviating from the first vascular region at anangular junction.

An angular junction could, for example, be the junction of theleft/right renal arteries and the aorta. Such an angular junctionrequires significant flexure of the apparatus in order to gain entryinto the respective left or right renal artery;

A force transmitting section is sized and configured to possess selectedmechanical properties that accommodate physical passage through and thetransmission of forces within the intravascular path. For example, as itleads from an accessed femoral artery (left or right), through therespective iliac branch artery and into the aorta, and in proximity tothe targeted renal artery (left or right).

The axis of the elongated shaft, as used above, refers to thelongitudinal access of the elongated shaft.

The proximal region of the apparatus refers to the proximal end regionof the elongated shaft. This region may include, for example, the handleand the force transmitting section of the apparatus.

The distal region or distal section of the apparatus refers to thedistal end region of the apparatus; the end of the apparatus that isfurthest away from the handle. The distal end region includes, forexample, a first or proximal flexure zone, a second or intermediateflexure zone, and/or a distal flexure zone.

The first flexure zone refers to the flexure zone that is closest to theproximal end region of the apparatus. The first flexure zone isequivalent to the proximal flexure zone (see discussion of FIGS. 11A to11C above). The first or proximal flexure zone is proximal to the handleor the force transmitting section, which is part of the proximal endregion.

The first flexure zone or proximal flexure zone may also be referred toas a proximal section. The proximal section may be flexible to enable itto be placed into the angular junction. For example, a proximal flexiblesection is adapted to bend within a guide catheter to form atransitional bend.

A transitional bend that is supported and stable within the vasculatureis defined as a proximal flexure zone or proximal section.

The second flexure zone refers to the flexure zone distal from the firstflexure zone (or proximal flexure zone). In embodiments having more thantwo flexure zones, the second flexure zone is equivalent to theintermediate flexure zone described in more detail above. The thermalelement may be supported by the second or intermediate flexure zone. Inembodiments having only two flexure zones, the second flexure zone isequivalent to the distal flexure zone outlined above.

The second flexure zone or intermediate flexure zone may also bereferred to as an intermediate section. The intermediate section may bedeflectable to enable it to extend distally from an angular junction.For example, an intermediate section may extend distally from atransitional bend of a flexible proximal section.

The third flexure zone refers to the flexure zone distal to the secondflexure zone (or intermediate flexure zone). The third flexure zone isequivalent to the distal flexure zone described in more detail above.The thermal element may be carried at the end of or coupled to thedistal flexure zone. The thermal element is positioned at the distal endor buttresses the distal end of the distal flexure zone.

The third flexure zone or distal flexure zone may also be referred to asa flexible distal section. The flexible distal section may extenddistally from an intermediate section, as described in more detailabove.

The thermal element may be any suitable element for thermal heating. Thethermal element is sized and configured for manipulation and use withina renal artery. The thermal element is coupled to or carried by thedistal flexure zone. Additionally, the distal flexure zone is configuredto orient a portion of the thermal element alongside a region of tissue,thereby providing consistent tissue contact at each treatment location.The distal flexure zone also biases the thermal heating element againsttissue, thereby stabilizing the thermal element.

The apparatus may further comprise a second thermal element coupled tothe second or intermediate flexure zone, wherein the second thermalelement is configured to contact the first wall region of the peripheralblood vessel.

The distal flexure zone separates the thermal element from the elongatedshaft. In certain embodiments of the disclosure, the apparatus may haveonly one flexure zone, i.e. a distal flexure zone. The distal flexurezone having the flexible structure creates a region of electricalisolation between the thermal element and the rest of the elongatedshaft, whereby the thermal element is operatively coupled to the rest ofthe apparatus via at least one supply wire.

In one embodiment, the distal flexure zone is approximately 2 to 5 mm inlength. In other embodiments, however, the distal flexure zone can be aslong as about 1 cm.

In some embodiments, the length of the intermediate flexure zone canrange from approximately 5 mm to 15 mm. In other embodiments,particularly for treatments in relatively long blood vessels, the lengthof the intermediate flexure zone can be as long as about 20 mm. Inanother embodiment, the length of the intermediate flexure zone can beabout 12.5 mm.

A flexure control element may be coupled to the first or second flexurezones, or proximal, or intermediate flexural zones. The flexure controlelement is configured to apply a force to the coupled zone such that thezone flexes in a radial direction from the axis of the longitudinal axisof the zone. The flexure control element may be carried by the handle.

A flexure controller is coupled to the flexure control element and canbe operated to cause the flexure control element to apply a first forcesuitable to flex or move the respective zone that is coupled to theflexure control element. The flexure controller may be part of orcoupled to the handle of the apparatus, catheter apparatus or device.

The flexure control element and flexure controller may be part of acontrol mechanism coupled to first, second, proximal, or intermediatezones. The control mechanism may include a flexure controller in theform of a control wire attached/coupled to the distal end portion of therespective zone. The control wire may be passed proximally through oralongside the elongated shaft of the apparatus/device and coupled to aflexure controller in the form of an actuator on or part of the handle.

Operation of the actuator by the caregiver pulling proximally on orpushing forward the actuator pulls the control wire back to apply acompressive and/or bending force to the coupled flexure zone resultingin bending. The compressive force in combination with the optionaldirectionally biased stiffness of the flexure zone deflects the flexurezone and, thereby, radially moves the flexure zone with respect to itslongitudinal axis.

Desirably, as described in more detail above, the distal end region ofthe elongated shaft can be sized and configured to vary the stiffness ofthe flexure zone(s) about its circumference. The variablecircumferential stiffness imparts preferential and directional bendingto the flexure zone (i.e., directionally biased stiffness). In responseto operation of the actuator, the flexure zone may be configured to bendin a single preferential direction. The compressive and/or bending forceand resulting directional bending from the deflection of the flexurezone has the consequence of altering the axial stiffness of the flexurezone. The actuation of the control wire serves to increase the axialstiffness of the flexure zone. The directionally biased stiffness of theflexure zone causes the flexure zone to move in a predetermined radialdirection in response to a first force applied by the flexure controlelement.

The stiffness of each of the flexure zones, such as the first and thesecond flexure zones, can apply via the thermal element a stabilizingforce that positions the thermal element in substantially secure contactwith the tissue surface during actuation of the flexure control element.This stabilizing force also influences the amount of tissue surfacecontact achieved by the thermal heating element (i.e., the ASA to TSAratio). In one embodiment, for example, the stabilizing force may causeat least twenty-five percent of the total surface area of the thermalelement to contact the tissue surface.

A second flexure element is part of or coupled to the distal flexurezone, which may be the second or third flexure zone. The second flexureelement is also coupled to the thermal element. The second flexureelement has mechanical properties that accommodate additional flexure orbending, independent of the proximal flexure zone and the intermediateflexure zone, at a preferred treatment angle α3. The second flexureelement may be or have a flexible structure.

A flexible structure accommodates passive flexure of the thermal elementin any plane through the axis of the elongated shaft. The thermalelement may flex up to ninety degrees, or less than or equal to ninetydegrees from the axis.

The flexible structure may be in the form of a thread, such as a polymerthread. It is desirable for thread be comprised of Kevlar or similarpolymer thread. The thread may be encased in or covered with a coatingor wrapping, such as a polymer coating. The thread may be covered with apolymer laminate, coating, or sheath that can be comprised of anyelectrically insulative material, and particularly those listed abovewith respect to the sheath (e.g., carbothane). The flexible structuremay further comprise a metal coil.

The thread may mechanically couple the flexible structure to at leastone of the thermal element and the elongated shaft. In one embodiment,the thread is routed through a proximal anchor, which is attached to thedistal end of a flexure zone (e.g., intermediate flexure zone), and adistal anchor, which is fixed within or integrated into the thermalelement using solder.

The flexible structure can include, for example, a spring-like flexibletubular structure as described in more detail above. Alternatively, theflexible structure may be in the form of a tubular metal coil, cable,braid or polymer. The flexible structure can take the form of an oval,rectangular, or flattened metal coil or polymer. In alternateembodiments, the flexible structure may comprise other mechanicalstructures or systems that allow the thermal element to pivot in atleast one plane of movement. For example, the flexible structure maycomprise a hinge or ball/socket combination.

Not under the direct control of the physician, passive flexure of thesecond flexure element at the distal flexure zone occurs in response tocontact between the thermal element and wall tissue occasioned by theradial deflection of the thermal element at the first, second orintermediate flexure zone.

The force transmitting section is sized and configured for transmittingalong a compound flexure or compound structure of the elongated shaft.

A compound structure in the elongated shaft is formed by the flexure ofthe proximal, intermediate, and distal flexure zones. The compoundstructure positions a thermal element carried by the distal flexure zonefor placement in contact with tissue along the intravascular path,

A connector on or carried by the handle is configured to connect thethermal element to a thermal energy source. The connector may be a cableplugged into or operatively attached to the handle. The energy sourcemay be a generator or any other energy source. At least one supply wiremay pass along the elongated shaft or through a lumen in the elongatedshaft from the cable plugged into or operatively attached to the handleto convey the energy to the thermal element.

The energy supplied to the thermal element may be at least one ofradiofrequency, microwave energy, ultrasound energy, laser/light energy,thermal fluid, and cryogenic fluid. The thermal element may be anelectrode for applying radiofrequency energy.

Additionally, a sensor such as a temperature sensor (e.g., thermocouple,thermistor, etc.), optical sensor, microsensor or impedance sensor canbe located adjacent to, on or within the thermal element. The sensor canmonitor a parameter of the apparatus and/or the tissue surface. Thesensor may be connected to one or more supply wires. With two supplywires, one wire could convey the energy to the thermal heating elementand one wire could transmit the signal from the sensor. Alternatively,both wires could transmit energy to the thermal heating element.

A feedback control system is configured to alter treatment delivered tothe tissue surface in response to the monitored parameter. The feedbackcontrol system may form part of the catheter or may be attached to theenergy source, such as a generator. The feedback control system may be aprocessor coupled to the catheter or the energy source. The sensor datacan be acquired or monitored by the feedback control system prior to,simultaneous with, or after the delivery of energy or in between pulsesof energy, when applicable. The monitored data may be used in a feedbackloop to better control therapy, e.g., to determine whether to continueor stop treatment, and it may facilitate controlled delivery of anincreased or reduced power or a longer or shorter duration therapy.

The feedback control system, such as the generator, can include analgorithm for controlling the delivery/output of energy to the thermalelement. The algorithm can be implemented, for example, as aconventional computer program for execution by a processor coupled tothe energy source.

The handle may comprise a rotating fitting coupled to the elongatedshaft and configured to rotate the elongated shaft about the axiswithout rotating the handle. The rotating fitting can comprise arotational limiting element configured to prevent rotation of theelongated shaft beyond a predetermined number of revolutions.

The rotational limiting element may be in the form of an axial grooveand the distal portion of the handle can include a fitting interfacehaving a helical channel. A traveling element, for example in the formof a ball comprising stainless steel, another metal, or a polymer, canbe placed within the fitting interface so that it, upon rotation of thefitting, may simultaneously travel within the helical channel of thefitting interface and along the axial groove of the fitting. When theball reaches the end of the channel and/or groove, the ball will nolonger move and, consequently, the fitting will not be able to rotateany further in that direction, i.e. the travel of the traveling elementis limited by the structural confines of the interface. The rotationalfitting and handle fitting interface can be configured to allow for theoptimal number of revolutions for the shaft, given structural ordimensional constraints (e.g., wires). For example, the components ofthe handle could be configured to allow for two revolutions of the shaftindependent of the handle.

A controlled flexure zone may comprise a first or proximal flexure zoneor second or intermediate flexure zone. The controlled flexure zonerefers to the part of the elongated shaft that may be controlled by aremotely controlled element. The controlled flexure zone may be in theform of a tubular structure.

A remotely controlled element may be in the form of, but is not limitedto, a control wire attached to the distal end of the controlled flexurezone. The control wire may be passed proximally through the elongatedshaft of the apparatus and coupled to an actuator on or part of thehandle. An operator may remotely operate the actuator by pullingproximally on or pushing forward the actuator and pulling the controlwire back to apply a compressive and/or bending force to the flexurezone resulting in bending. The compressive force in combination with theoptional directionally biased stiffness of the controlled flexure zonedeflects the controlled flexure zone and, thereby, radially moves thecontrolled flexure zone with respect to its longitudinal axis.

Desirably, as described in more detail above, the distal end region ofthe elongated shaft can be sized and configured to vary the stiffness ofthe flexure zone(s) about its circumference. The variablecircumferential stiffness imparts preferential and directional bendingto the controlled flexure zone (i.e., directionally biased stiffness).This enables the flexure of the controlled flexure zone in apredetermined radial direction. In response to operation of theactuator, the controlled flexure zone may be configured to bend in asingle preferential direction. The compressive and bending force andresulting directional bending from the deflection of the controlledflexure zone has the consequence of altering the axial stiffness of thecontrolled flexure zone. The actuation of the control wire serves toincrease the axial stiffness of the controlled flexure zone. Thedirectionally biased stiffness of the controlled flexure zone causes theflexure zone to move in a predetermined radial direction in response toa first force applied by the flexure control element.

The stiffness of the controlled zone can apply via the thermal element astabilizing force that positions the thermal element in substantiallysecure contact with the tissue surface, during actuation of the flexurecontrol element. This stabilizing force also influences the amount oftissue surface contact achieved by the thermal heating element (i.e.,the ASA to TSA ratio). In one embodiment, for example, the stabilizingforce may cause at least twenty-five percent of the total surface areaof the thermal element to contact the tissue surface.

The controlled flexure zone in the form of a tubular structure mayprovide the directionally biased stiffness. The tubular structure may bemade of a metal material, e.g. of stainless steel, or a shape memoryalloy, e.g., nickel titanium (a.k.a., nitinol or NiTi), to possess therequisite axial stiffness and torsional stiffness. The tubular structuremay comprise a tubular polymer or metal/polymer composite havingsegments with different stiffnesses. The tubular structure may be in theform of an oval, or rectangular, or flattened metal coil or polymerhaving segments with different stiffnesses.

The tubular structure, when made from metal, may be laser cut. Forexample, the tubular structure may be laser cut along its length toprovide a bendable, spring-like structure. The tubular structure caninclude a laser-cut pattern having a spine with a plurality ofconnecting ribs. The pattern biases the deflection of the tubularstructure, in response to pulling on the control flexure element coupledto the distal end of the tubular structure, toward a desired direction.The directionally-biased stiffness of the tubular structure may bedetermined by the location of the spine in relation to the plurality ofconnecting ribs on the tubular structure.

The tubular structure may further comprise a polymer laminate, coating,or sheath.

An unrestrained flexure zone is distal to the controlled flexure zone.The unrestrained flexure zone has or is coupled to a thermal or tissueheating element. The unrestrained flexure zone has mechanical propertiesthat accommodate additional flexure or bending, independent to or inresponse to the flexure of the controlled flexure zone. The unrestrainedflexure zone may have or be coupled to a flexible structure as describedin more detail above.

The apparatus may further comprise a second thermal element coupled tothe controlled flexure zone, wherein the second thermal element isconfigured to contact the first wall region of the peripheral bloodvessel.

A connector on or carried by the handle is configured to connect thethermal element to a thermal energy source. The connector may be a cableplugged into or operatively attached to the handle. The energy sourcemay be a generator or any other energy source. At least one supply wiremay pass along the elongated shaft or through a lumen in the elongatedshaft from the cable plugged into or operatively attached to the handleconvey the energy to the thermal element.

The elongated shaft may be configured for rotation within the peripheralblood vessel when the controlled flexure zone is in flexure against thefirst wall region and when the thermal element is in contact with thesecond wall region. Rotation of the elongated shaft positions thecontrolled flexure zone against a third wall region and positions thethermal element against a fourth wall region, wherein the third wallregion is circumferentially offset from the first wall region and thefourth wall region is circumferentially offset from the second wallregion, and wherein the third wall region is generally opposite thefourth wall region.

As described in more detail above, the apparatus of the disclosure mayform part of a system. The system may further comprise instructions thatcommand the energy generator/source to deliver energy to the thermalelement according to a predetermined energy delivery profile. Thepredetermined energy delivery profile may comprise increasing energydelivery to a predetermined power level for a first period of time,maintaining energy delivery at the first power level for a second periodof time; and increasing energy delivery to a second power level if thetemperature value is less than a preset threshold following the secondperiod of time.

As described in more detail above, the apparatus of the disclosure maybe provided in the form of a kit, such as a medical kit. The kit mayfurther comprise a cable configured to electrically connect the catheterapparatus to the thermal energy source and a dispersive electrodeconfigured to provide a return path for an energy field from thecatheter. The kit may further comprise one or more guide catheters(e.g., a renal guide catheter). The cable can also be integrated intothe apparatus such that both components are packaged together. Eachcomponent may have its own sterile packaging (for components requiringsterilization) or the components may have dedicated sterilizedcompartments within the kit packaging.

The kit may further comprise instructions for delivering the catheterapparatus into a renal artery of the patient and at least partiallydenervating the kidney corresponding to the renal artery to treat thepatient for a condition associated with at least one of hypertension,heart failure, kidney disease, chronic renal failure, sympathetichyperactivity, diabetes, metabolic disorder, arrhythmia, acutemyocardial infarction and cardio-renal syndrome

VIII. Conclusion

The above detailed descriptions of embodiments of the invention are notintended to be exhaustive or to limit the invention to the precise formdisclosed above. Although specific embodiments of, and examples for, theinvention are described above for illustrative purposes, variousequivalent modifications are possible within the scope of the invention,as those skilled in the relevant art will recognize. For example, whilesteps are presented in a given order, alternative embodiments mayperform steps in a different order. The various embodiments describedherein can also be combined to provide further embodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the invention. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.For example, much of the disclosure herein describes a thermal heatingelement 24 or electrode 46 in the singular. It should be understood thatthis application does not exclude two or more thermal heating elementsor electrodes. In one embodiment representative of a multi-electrodeconfiguration, a second electrode could be placed on the intermediateflexure zone 34 opposite the direction of deflection of the intermediateflexure zone 34 such that the second electrode could deliver treatmentto the vessel wall at or near contact region 124. This approach wouldallow two spaced apart treatments per position of the treatment device,one distal treatment via the first electrode 46 and one proximaltreatment via the second electrode.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the invention. Accordingly, the invention is notlimited except as by the appended claims.

1-31. (canceled)
 32. A catheter apparatus, comprising: an elongatedshaft extending along an axis and comprising a controlled flexure zoneand an unrestrained flexure zone coupled to and extending distally fromthe controlled flexure zone, the elongated shaft sized and configuredfor intravascular delivery into a renal blood vessel; wherein theunrestrained flexure zone is configured to carry the thermal element;wherein the controlled flexure zone is sized and configured forplacement into contact against a first wall region of the renal bloodvessel and, in response to application of a force applied by a remotelycontrolled element, for flexure relative to the axis in a predeterminedradial direction away from the first wall region toward a second wallregion of the renal blood vessel generally opposite to the first wallregion; wherein the unrestrained flexure zone is sized and configured,when the controlled flexure zone is in flexure against the first wallregion, for unrestrained flexure relative to the axis to place a side ofthe thermal element into contact against the second wall region; andwherein the controlled flexure zone is configured to apply, when inflexure against the first wall region, through the unrestrained flexurezone a stabilizing force to the thermal element against the second wallregion.
 33. The catheter apparatus of claim 32 wherein the thermalelement comprises a first thermal element, and wherein the catheterapparatus further comprises a second thermal element coupled to thecontrolled flexure zone, wherein the second thermal element isconfigured to contact the first wall region of the renal blood vessel.34. The catheter apparatus of claim 32 wherein the elongated shaft isconfigured for rotation within the renal blood vessel when thecontrolled flexure zone is in flexure against the first wall region andwhen the thermal element is in contact with the second wall region,wherein rotation of the elongated shaft positions the controlled flexurezone against a third wall region and positions the thermal elementagainst a fourth wall region, wherein the third wall region iscircumferentially offset from the first wall region and the fourth wallregion is circumferentially offset from the second wall region, andwherein the third wall region is generally opposite the fourth wallregion.
 35. The catheter apparatus of claim 32 wherein the remotelycontrolled element comprises a wire coupled to a distal portion of thecontrolled flexure zone, and wherein the force applied by the wire is abending or compressive force against the controlled flexure zone. 36.The catheter apparatus of claim 32 wherein the controlled flexure zonecomprises a tubular structure having a directionally-biased stiffness.37. The catheter apparatus of claim 36 wherein the tubular structurecomprises a laser-cut metal tube.
 38. The catheter apparatus of claim 37wherein the laser-cut metal tube comprises a spine and a plurality ofribs, and wherein the directionally-biased stiffness of the tubularstructure is determined by the location of the spine in relation to theplurality of ribs on the tubular structure.
 39. The catheter apparatusof claim 32 wherein the tubular structure further comprises a polymerlaminate, coating or sheath.
 40. The catheter apparatus of claim 32,further comprising a sensor adjacent to, on, or within the thermalelement, and wherein the sensor is configured to monitor a parameter ofat least one of the apparatus and the renal blood vessel.
 41. Thecatheter apparatus of claim 40 wherein the sensor comprises at least oneof a temperature sensor, impedance sensor, optical sensor or microsensor.
 42. The catheter apparatus of claim 40, further comprising afeedback control system configured to alter treatment delivered to thetissue surface in response to the monitored parameter.
 43. The catheterapparatus of claim 42 wherein the feedback control system comprises analgorithm for controlling output of the thermal element.
 44. Thecatheter apparatus of claim 32 wherein the thermal element is configuredto apply treatment to neural tissue adjacent to the renal blood vesselusing at least one of radiofrequency energy, microwave energy,ultrasound energy, laser/light energy, thermal fluid, and cryogenicfluid.
 45. The catheter apparatus of claim 32 wherein the thermalelement comprises an electrode for applying radiofrequency energy totissue.
 46. (canceled)
 47. (canceled)
 48. The catheter apparatus ofclaim 32 wherein the controlled flexure zone has a length of from about5 millimeters to about 15 millimeters.
 49. The catheter apparatus ofclaim 43 wherein the algorithm comprises instructions for deliveringenergy to the thermal element according to a predetermined energydelivery profile, and wherein the predetermined energy delivery profilecomprises: increasing energy delivery to a predetermined first powerlevel over a first period of time; maintaining energy delivery at thefirst power level for a second period of time; and increasing energydelivery to a predetermined second power level if a temperature value ofa treatment site or of the thermal element is less than a presetthreshold temperature following the second period of time.
 50. Thecatheter apparatus of claim 32 wherein the thermal element has an outerdiameter of from approximately 0.049 inches to 0.051 inches.
 51. Thecatheter apparatus of claim 32 wherein the unrestrained flexure zone hasa first length and the controlled flexure zone has a second length lessthan the first length.
 52. The catheter apparatus of claim 32 whereinthe thermal element comprises a single electrode for applyingradiofrequency energy to the tissue, and wherein the electrode comprisesa generally circular cylinder having a length and a diameter less thanthe length.
 53. The catheter apparatus of claim 32 wherein thestabilizing force causes at least 25% of a total surface area of thethermal element to contact the second wall region.
 54. A medicaltreatment kit, comprising: an intravascular treatment device including—an elongated shaft extending along an axis and comprising a controlledflexure zone and an unrestrained flexure zone coupled to and extendingdistally from the controlled flexure zone, the elongated shaft sized andconfigured for intravascular delivery into a renal blood vessel; whereinthe unrestrained flexure zone is configured to carry the thermalelement; wherein the controlled flexure zone is sized and configured forplacement into contact against a first wall region of the renal bloodvessel and, in response to application of a force applied by a remotelycontrolled element, for flexure relative to the axis in a predeterminedradial direction away from the first wall region toward a second wallregion of the renal blood vessel generally opposite to the first wallregion; wherein the unrestrained flexure zone is sized and configured,when the controlled flexure zone is in flexure against the first wallregion, for unrestrained flexure relative to the axis to place a side ofthe thermal element into contact against the second wall region; andwherein the controlled flexure zone is configured to apply, when inflexure against the first wall region, through the unrestrained flexurezone a stabilizing force to the thermal element against the second wallregion; a cable configured to electrically connect the intravasculartreatment device to an energy generator; a guide catheter configured tofacilitate intravascular delivery of the treatment device into apatient; and instructions for delivering the treatment device into arenal artery of the patient and at least partially denervating a kidneyof the patient corresponding to the renal artery to treat the patientfor a condition associated with at least one of hypertension, heartfailure, kidney disease, chronic renal failure, sympathetichyperactivity, diabetes, metabolic disorder, arrhythmia, acutemyocardial infarction and cardio-renal syndrome.
 55. The medicaltreatment kit of claim 54, further comprising a dispersive electrodeconfigured to provide a return path for an energy field from thetreatment device.
 56. The medical treatment kit of claim 54 wherein: theelongated shaft comprises a proximal end region and a distal end region,the distal end region including the controlled flexure zone and theunrestrained flexure zone coupled to and extending distally from thecontrolled flexure zone; and the intravascular treatment device furthercomprises a handle carried by the proximal end region of the elongatedshaft, wherein the cable is integral with the handle.
 57. The medicaltreatment kit of claim 54 wherein: the elongated shaft comprises aproximal end region and a distal end region, the distal end regionincluding the controlled flexure zone and the unrestrained flexure zonecoupled to and extending distally from the controlled flexure zone; andthe intravascular treatment device further comprises a handle carried bythe proximal end region of the elongated shaft, wherein the cable andthe treatment device are discrete elements configured to be releasablyconnected to each other, and wherein the cable is configured to beconnected to the handle of the treatment device.